GOLDEN-3: Efficacy and Safety Trial of 12 Weeks of Treatment With Nebulized SUN-101 in Patients With COPD

• Sponsor: Sunovion Respiratory Development Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02347761
• Collaborator: (none)
• Enrollment: 653
• Locations: 44
• Arms: 3
• Duration (Months): 9
• Patients Per Site: 14.8
• Patients Per Site Per Month: 1.7

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	Drug: SUN-101 50 mcg BID eFlow (CS) nebulizer; Drug: SUN-101 25 mcg BID eFlow (CS) nebulizer; Drug: Placebo BID eFlow Closed System (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. Approximately 150 subjects will be enrolled in the substudy (at selected sites only). These subjects will be required to participate in serial spirometry, vital signs, ECGs, and an additional Holter monitor assessment at Visit 6 (Week 12). This subset of subjects will be referred to as the Substudy Population.

Study Design

• Study Type: Interventional
• Actual Enrollment: 653 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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-3 (Glycopyrrolate for Obstructive Lung Disease Via Electronic Nebulizer)
• Study Start Date: Feb 1, 2015
• Actual Primary Completion Date: Nov 1, 2015
• Actual Study Completion Date: Nov 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SUN-101 50 mcg BID eFlow (CS) nebulizer SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer	Drug: SUN-101 50 mcg BID eFlow (CS) nebulizer; SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer
Experimental: SUN-101 25 mcg BID eFlow (CS) nebulizer SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer	Drug: SUN-101 25 mcg BID eFlow (CS) nebulizer; SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer
Placebo Comparator: Placebo BID eFlow (CS) nebulizer Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer	Drug: Placebo BID eFlow Closed System (CS) nebulizer; Placebo twice daily (BID) eFlow 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.Change from baseline in trough FEV1 was calculated as the trough FEV1 value at Week 12 minus the morning trough FEV1 at baseline (mean of the two pre-dose values at 45 and 15 minutes prior to the first 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) "ALL COLLECTED" and "ON TREATMENT" data are the same. The only difference is in the number of visits included for those participants who may have discontinued randomized treatment but remained in the study." for all endpoints

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

   ON TEATMENT-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.Change from baseline in trough FEV1 was calculated as the trough FEV1 value at Week 12 minus the morning trough FEV1 at baseline (mean of the two pre-dose values at 45 and 15 minutes prior to the first 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. Standardized Change From Baseline at Week 12 in FEV1 Area Under the Curve (AUC) (0-12) in the Substudy Population [Baseline and Week 12]

   ALL COLLECTED The standardized FEV1 AUC(0-12) was calculated at weeks 0 and 12 for the Substudy Population with extended spirometry measurements. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time. Intermittent missing spirometry measurements were ignored and the trapezoidal rule would simply span the missing time point(s). If the Hour 12 time point was missing, then the AUC(0-12) calculation was based on the time interval up to the last non-missing time point prior to Hour 12. If a subject has a missing baseline FEV1, then that subject had a missing AUC. 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. Standardized Change From Baseline at Week 12 in FEV1 Area Under the Curve (AUC) (0-12) in Substudy Population [Baseline and Week 12]

   ON TREATMENT The standardized FEV1 AUC(0-12) was calculated at weeks 0 and 12 for the Substudy Population with extended spirometry measurements. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time. Intermittent missing spirometry measurements were ignored and the trapezoidal rule would simply span the missing time points. If the Hour 12 time point was missing, then the AUC(0-12) calculation was based on the time interval up to the last non-missing time point prior to Hour 12. If a subject has a missing baseline FEV1, then that subject had a missing AUC.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 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

4. 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. Change from baseline in trough FVC was calculated as the trough FVC value at Week 12 minus the morning trough FVC at baseline (mean of the two pre-dose values at 45 and 15 minutes prior to the first 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).

5. 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).

6. 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).

7. 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).

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

   ALL COLLECTED 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)

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

   ALL COLLECTED 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)

10. 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.

11. Percent 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.

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

    ON TREATMENT 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

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

    ON TREATMENT 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

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

    ON TREATMENT 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.

15. Percent of Subjects Who Discontinue Treatment Due to TEAE [Week 0-12]

    ON TREATMENT 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.

16. Incidence Rate Per 100 Person-years of Subjects With Treatment Emergent Adverse Events (TEAE) [Week 0-12]

    ALL COLLECTED 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)I ncidence 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 ongoing 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	Pinnacle Research Group, LLC	Anniston	Alabama	United States	36207
2	Pulmonary Associates, PA	Phoenix	Arizona	United States	85006
3	Clinical Research Consortium - Arizona	Tempe	Arizona	United States	85283
4	Desert Sun Clinical Research, LLC	Tucson	Arizona	United States	85710
5	Western States Clinical Research, Inc.	Wheat Ridge	Colorado	United States	80033
6	Clinical Research of West Florida, Inc.	Clearwater	Florida	United States	33765
7	Clermont Medical Research	Clermont	Florida	United States	34711
8	Riverside Clinical Research	Edgewater	Florida	United States	32132
9	Pulmonary Disease Specialists, PA, d/b/a PDS Research	Kissimmee	Florida	United States	34741
10	AppleMed Research, Inc.	Miami	Florida	United States	33155
11	Clinical Trials of Florida, LLC	Miami	Florida	United States	33186
12	Florida Institute for Clinical Research, LLC	Orlando	Florida	United States	32825
13	Emerald Coast Research Associates	Panama City	Florida	United States	32405
14	Clinical Research of West Florida, Inc	Tampa	Florida	United States	33603
15	Abraham Reasearch, PLLC	Fort Mitchell	Kentucky	United States	41017
16	Pulmonary Research Institute of Southeast Michigan	Livonia	Michigan	United States	48152
17	Minnesota Lung Center	Edina	Minnesota	United States	55435
18	Minnesota Lung Center	Woodbury	Minnesota	United States	55125
19	Midwest Chest Consultants, P.C.	Saint Charles	Missouri	United States	63301
20	Clinical Research Consortium	Las Vegas	Nevada	United States	89119
21	AAIR Research Center	Rochester	New York	United States	14618
22	American Health Research, Inc.	Charlotte	North Carolina	United States	28207
23	Hickory Research Center	Hickory	North Carolina	United States	28602
24	North Carolina Clinical Research	Raleigh	North Carolina	United States	27607
25	PMG Research of Wilmington	Wilmington	North Carolina	United States	28401
26	Columbus Regional Research Institute	Columbus	Ohio	United States	31904
27	Columbus Clinical Research, Inc	Columbus	Ohio	United States	43213
28	Optimed Research, LTD	Columbus	Ohio	United States	43235
29	Clinical Research Institute of Southern Oregon, PC	Medford	Oregon	United States	97504
30	Research Protocol Management Specialists	Pittsburgh	Pennsylvania	United States	15243
31	Safe Harbor Clinical Research	East Providence	Rhode Island	United States	02914
32	Palmetto Medical Research Associates, LLC	Easley	South Carolina	United States	29640
33	Greenville Pharmaceutical Research, Inc	Greenville	South Carolina	United States	29615
34	Upstate Pharmaceutical Research	Greenville	South Carolina	United States	29615
35	Piedmont Research Partners, LLC	Indian Land	South Carolina	United States	29707
36	S. Carolina Pharmaceutical Research	Spartanburg	South Carolina	United States	29303
37	Spartanburg Medical Research	Spartanburg	South Carolina	United States	29303
38	CU Pharmaceutical Research	Union	South Carolina	United States	29379
39	Texas Pulmonary and Critical Care Consultants, PA	Fort Worth	Texas	United States	76104
40	Pioneer Research Solutions, Inc.	Houston	Texas	United States	77099
41	Central Texas Health Research	New Braunfels	Texas	United States	78130
42	Sylvana Research Associates	San Antonio	Texas	United States	78229
43	Pulmonary Research of Abingdon, LLC	Abingdon	Virginia	United States	24210
44	Pulmonary Associates of Richmond, Inc.	Richmond	Virginia	United States	23225

Sponsors and Collaborators

• Sunovion Respiratory Development Inc.

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sunovion Respiratory Development Inc.
• ClinicalTrials.gov Identifier: NCT02347761
• Other Study ID Numbers: SUN101-301
• First Posted: Jan 27, 2015
• Last Update Posted: Mar 22, 2018
• Last Verified: Feb 1, 2018

• Keywords provided by Sunovion Respiratory Development Inc.: Chronic Obstructive Pulmonary Disease

Study Results

Participant Flow

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Period Title: All Collected
STARTED	218	217	218
COMPLETED	201	203	191
NOT COMPLETED	17	14	27
Period Title: All Collected
STARTED	218	217	218
COMPLETED	191	194	176
NOT COMPLETED	27	23	42

Baseline Characteristics

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer	Total
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer	Total of all reporting groups
Overall Participants	218	217	218	653
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	135 61.9%	122 56.2%	109 50%	366 56%
>=65 years	83 38.1%	95 43.8%	109 50%	287 44%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	62.5 (8.09)	63.1 (8.78)	63.7 (8.37)	63.1 (8.42)
Sex: Female, Male (Count of Participants)
Female	98 45%	99 45.6%	107 49.1%	304 46.6%
Male	120 55%	118 54.4%	111 50.9%	349 53.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 2.8%	7 3.2%	6 2.8%	19 2.9%
Not Hispanic or Latino	212 97.2%	210 96.8%	212 97.2%	634 97.1%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.5%	1 0.5%	1 0.5%	3 0.5%
Asian	0 0%	1 0.5%	1 0.5%	2 0.3%
Native Hawaiian or Other Pacific Islander	1 0.5%	0 0%	0 0%	1 0.2%
Black or African American	18 8.3%	15 6.9%	20 9.2%	53 8.1%
White	198 90.8%	200 92.2%	196 89.9%	594 91%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	218 100%	217 100%	218 100%	653 100%
cardiovascular risk (low/high) and categories for high caridovascular risk (Count of Participants)
low cardiovascular risk	77 35.3%	78 35.9%	76 34.9%	231 35.4%
high cardiovascular risk	141 64.7%	139 64.1%	142 65.1%	422 64.6%
cerebrovascular disease	10 4.6%	13 6%	14 6.4%	37 5.7%
peripheral arterial disease	10 4.6%	13 6%	14 6.4%	37 5.7%
clinically significant arrhythmia	7 3.2%	13 6%	2 0.9%	22 3.4%
heart failure	9 4.1%	7 3.2%	8 3.7%	24 3.7%
hyertension	127 58.3%	128 59%	138 63.3%	393 60.2%
background long-acting beta(2) agonist (LABA) use (Count of Participants)
background LABA use =yes	68 31.2%	66 30.4%	63 28.9%	197 30.2%
background LABA use =no	150 68.8%	151 69.6%	155 71.1%	456 69.8%
Forced expiratory volume in one second (FEV1) (liters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [liters]	1.3745 (0.52957)	1.3108 (0.50243)	1.3122 (0.47511)	1.3325 (0.50297)

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.Change from baseline in trough FEV1 was calculated as the trough FEV1 value at Week 12 minus the morning trough FEV1 at baseline (mean of the two pre-dose values at 45 and 15 minutes prior to the first 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) "ALL COLLECTED" and "ON TREATMENT" data are the same. The only difference is in the number of visits included for those participants who may have discontinued randomized treatment but remained in the study." for all endpoints
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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Least Squares Mean (Standard Error) [liters]	0.0961 (0.01371)	0.0886 (0.01369)	-0.0075 (0.01397)

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 for repeated measures including terms for treatment, cardiovascular risk, background LABA use, visit, visit 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	The primary null hypothesis for this study is that the mean change from baseline in trough FEV1 at Week 12 for the SUN-101 50 mcg dose is equal to the mean change from baseline in trough FEV1 at Week 12 for Placebo.
	Method	MMixed Model Repeat Measurement
	Comments	to control the family-wise Type I error rate,the Hochberg procedure(a tree-structured gatekeeping procedure)was used for comparisons of this endpoint
Method of Estimation	Estimation Parameter	Least Squares Mea Difference (SE)
	Estimated Value	0.1036
	Confidence Interval	(2-Sided) 95%; 0.0663 to 0.1409
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.01900
	Estimation Comments	standard error of the least squares mean

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SUN-101 25 mcg BID eFlow (CS) Nebulizer, Placebo BID eFlow (CS) Nebulizer
	Comments	The change from baseline in trough FEV1 was analyzed using a mixed model for repeated measures including terms for treatment, cardiovascular risk, background LABA use, visit, visit 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	The primary null hypothesis for this study is that the mean change from baseline in trough FEV1 at Week 12 for the SUN-101 50 mcg dose is equal to the mean change from baseline in trough FEV1 at Week 12 for Placebo.
	Method	Mixed Model Repeat Measurement
	Comments	to control the family-wise Type I error rate,the Hochberg procedure(a tree-structured gatekeeping procedure)was used for comparisons of the endpoint.
Method of Estimation	Estimation Parameter	Least Squares Mean Difference (SE)
	Estimated Value	0.0961
	Confidence Interval	(2-Sided) 95%; 0.0589 to 0.1334
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.01896
	Estimation Comments	Standard error of the least squares mean

2. Primary Outcome

Title	Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) Week 12
Description	ON TEATMENT-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.Change from baseline in trough FEV1 was calculated as the trough FEV1 value at Week 12 minus the morning trough FEV1 at baseline (mean of the two pre-dose values at 45 and 15 minutes prior to the first 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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Least Squares Mean (Standard Error) [liters]	0.1025 (0.01497)	0.0814 (0.01475)	-0.0238 (0.01534)

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 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
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 squares mean (SE)
	Comments
Method of Estimation	Estimation Parameter	Least Squares Mean (SE)
	Estimated Value	0.1264
	Confidence Interval	(2-Sided) 95%; 0.0856 to 0.1672
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.02076
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	SUN-101 25 mcg BID eFlow (CS) Nebulizer, Placebo BID eFlow (CS) Nebulizer
	Comments	The change from baseline in trough FEV1 was analyzed using 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	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 Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	LS mean (SE)
	Comments
Method of Estimation	Estimation Parameter	LS mean (SE)
	Estimated Value	0.1052
	Confidence Interval	(2-Sided) 95%; 0.0647 to 0.1457
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.02060
	Estimation Comments

3. Secondary Outcome

Title	Standardized Change From Baseline at Week 12 in FEV1 Area Under the Curve (AUC) (0-12) in the Substudy Population
Description	ALL COLLECTED The standardized FEV1 AUC(0-12) was calculated at weeks 0 and 12 for the Substudy Population with extended spirometry measurements. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time. Intermittent missing spirometry measurements were ignored and the trapezoidal rule would simply span the missing time point(s). If the Hour 12 time point was missing, then the AUC(0-12) calculation was based on the time interval up to the last non-missing time point prior to Hour 12. If a subject has a missing baseline FEV1, then that subject had a missing AUC. 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

The Substudy Population consisted of all ITT subjects who participated in post-dose serial measurements

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	62	49	42
Least Squares Mean (Standard Error) [liters]	0.0749 (0.02638)	0.0579 (0.3011)	-0.0474 (0.03229)

4. Secondary Outcome

Title	Standardized Change From Baseline at Week 12 in FEV1 Area Under the Curve (AUC) (0-12) in Substudy Population
Description	ON TREATMENT The standardized FEV1 AUC(0-12) was calculated at weeks 0 and 12 for the Substudy Population with extended spirometry measurements. The trapezoidal rule was used to calculate FEV1 AUC and then normalized to the length of time. Intermittent missing spirometry measurements were ignored and the trapezoidal rule would simply span the missing time points. If the Hour 12 time point was missing, then the AUC(0-12) calculation was based on the time interval up to the last non-missing time point prior to Hour 12. If a subject has a missing baseline FEV1, then that subject had a missing AUC.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

The Substudy Population consisted of all ITT subjects who participated in post-dose serial measurements, including serial spirometry, serial ECGs, serial vital sign measurements, as well as Holter monitoring at Visit 6.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	62	49	42
Least Squares Mean (Standard Error) [liters]	0.0708 (0.02792)	0.0496 (0.03280)	-0.0527 (0.03450)

5. 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
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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Least Squares Mean (Standard Error) [liters]	0.1476 (0.02226)	0.1515 (0.02220)	0.0147 (0.2266)

6. 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. Change from baseline in trough FVC was calculated as the trough FVC value at Week 12 minus the morning trough FVC at baseline (mean of the two pre-dose values at 45 and 15 minutes prior to the first 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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Least Squares Mean (Standard Error) [liters]	0.1566 (0.02392)	0.1393 (0.02353)	-0.0101 (0.2450)

7. 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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Least Squares Mean (Standard Error) [scores on a scale]	-2.363 (0.8344)	-4.250 (0.8211)	-0.844 (0.8396)

8. 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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Least Squares Mean (Standard Error) [scores on a scale]	-2.538 (0.8391)	-3.762 (0.8187)	-0.690 (0.8535)

9. 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 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 eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Least Squares Mean (Standard Error) [puffs (medication used)]	-0.815 (0.1234)	-0.609 (0.1259)	-0.632 (0.1257)

10. Secondary Outcome

Title	Number of Subjects With Major Adverse Cardiac Events (MACE)
Description	ALL COLLECTED 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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
MACE score	3 1.4%	0 0%	0 0%
Cardiovascular Death	1 0.5%	0 0%	0 0%
non-fatal myocardial infraction	1 0.5%	0 0%	0 0%
non-fatal stroke	1 0.5%	0 0%	0 0%

11. Secondary Outcome

Title	Percentage of Subjects With Major Cardiac Events (MACE)
Description	ALL COLLECTED 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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
MACE score	1.4 0.6%	0 0%	0 0%
Cardiovascular Death	0.5 0.2%	0 0%	0 0%
non-fatal myocardial infraction	0.5 0.2%	0 0%	0 0%
non-fatal stroke	0.5 0.2%	0 0%	0 0%

12. 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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Number [participants]	105 48.2%	86 39.6%	114 52.3%

13. Secondary Outcome

Title	Percent 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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Number [percentage of participants]	48.2 22.1%	39.6 18.2%	52.3 24%

14. Secondary Outcome

Title	Number of Subjects With Treatment Emergent Serious Adverse Events (SAE)
Description	ON TREATMENT 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

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Number [participants]	10 4.6%	8 3.7%	11 5%

15. Secondary Outcome

Title	Percent of Subjects With Treatment Emergent Serious Adverse Events (SAE)
Description	ON TREATMENT 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

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Number [percentage of participants]	4.6 2.1%	3.7 1.7%	5.0 2.3%

16. Secondary Outcome

Title	Number of Subjects Who Discontinue Treatment Due to TEAE
Description	ON TREATMENT 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 meidcation

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Number [participants]	8 3.7%	7 3.2%	21 9.6%

17. Secondary Outcome

Title	Percent of Subjects Who Discontinue Treatment Due to TEAE
Description	ON TREATMENT 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 meidcation

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
Number [percentage of participants]	3.7 1.7%	3.2 1.5%	9.6 4.4%

18. Secondary Outcome

Title	Incidence Rate Per 100 Person-years of Subjects With Treatment Emergent Adverse Events (TEAE)
Description	ALL COLLECTED 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)I ncidence 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.

Arm/Group Title	SUN-101 50 mcg BID eFlow (CS) Nebulizer	SUN-101 25 mcg BID eFlow (CS) Nebulizer	Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer	Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
Measure Participants	218	217	218
MACE score	45.5	0	0
Cardiovascular Death	15.2	0	0
non-fatal myocardial infraction	15.2	0	0
non-fatal stroke	15.2	0	0

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 does 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 eFlow (CS) Nebulizer		Placebo BID eFlow (CS) Nebulizer
Arm/Group Description	SUN-101 50 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 50 mcg BID eFlow (CS) nebulizer: SUN-101 50 mcg twice daily (BID) eFlow Closed System (CS) nebulizer		SUN-101 25 mcg twice daily (BID) eFlow (R) Closed System (CR) nebulizer SUN-101 25 mcg BID eFlow (CS) nebulizer: SUN-101 25 mcg twice daily (BID) eFlow Closed System (CS) nebulizer		Placebo twice daily (BID) eFlow (R) Closed System (CR) nebulizer Placebo BID eFlow Closed System (CS) nebulizer: Placebo twice daily (BID) eFlow Closed System (CS) nebulizer
All Cause Mortality
	SUN-101 50 mcg BID eFlow (CS) Nebulizer		SUN-101 25 mcg BID eFlow (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 eFlow (CS) Nebulizer		Placebo BID eFlow (CS) Nebulizer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/218 (4.6%)		8/217 (3.7%)		11/218 (5%)
Cardiac disorders
angina pectoris	0/218 (0%)	0	1/217 (0.5%)	1	0/218 (0%)	0
angina unstable	1/218 (0.5%)	1	0/217 (0%)	0	1/218 (0.5%)	1
coronary artery stenosis	0/218 (0%)	0	1/217 (0.5%)	1	0/218 (0%)	0
diastolic dysfunction	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
Gastrointestinal disorders
small intestinal obstruction	0/218 (0%)	0	1/217 (0.5%)	1	0/218 (0%)	0
General disorders
chest pain	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
Hepatobiliary disorders
gallbladder necrosis	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
Immune system disorders
pneumonia	2/218 (0.9%)	2	0/217 (0%)	0	0/218 (0%)	0
Infections and infestations
bronchitis	0/218 (0%)	0	0/217 (0%)	0	1/218 (0.5%)	1
emphysematous cholecystitis	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
lobar pheumonia	0/218 (0%)	0	0/217 (0%)	0	1/218 (0.5%)	1
pyelonephritis	0/218 (0%)	0	1/217 (0.5%)	1	0/218 (0%)	0
septic shock	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
Injury, poisoning and procedural complications
intentional overdose	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
subdural haematoma	0/218 (0%)	0	0/217 (0%)	0	1/218 (0.5%)	1
Investigations
antiphospholiid antibodies	0/218 (0%)	0	0/217 (0%)	0	1/218 (0.5%)	1
Metabolism and nutrition disorders
dehydration	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
diabetes mellitus inadequate control	0/218 (0%)	0	0/217 (0%)	0	1/218 (0.5%)	1
Musculoskeletal and connective tissue disorders
arthralgia	0/218 (0%)	0	0/217 (0%)	0	1/218 (0.5%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
lung adenocarcinoma stage IV	0/218 (0%)	0	1/217 (0.5%)	1	0/218 (0%)	0
malignant neoplasm of pleura metastatic	0/218 (0%)	0	0/217 (0%)	0	1/218 (0.5%)	1
Nervous system disorders
carotid artery stenosis	0/218 (0%)	0	1/217 (0.5%)	1	0/218 (0%)	0
lacunar infarction	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
transient ischaemic attack	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
Renal and urinary disorders
nephrolithiasis	0/218 (0%)	0	0/217 (0%)	0	1/218 (0.5%)	1
obstructive uropathy	0/218 (0%)	0	1/217 (0.5%)	1	0/218 (0%)	0
renal failure acute	0/218 (0%)	0	0/217 (0%)	0	1/218 (0.5%)	1
Respiratory, thoracic and mediastinal disorders
acute respiratory failure	0/218 (0%)	0	0/217 (0%)	0	1/218 (0.5%)	1
chronic obstructive pulmonary disease	4/218 (1.8%)	4	2/217 (0.9%)	2	2/218 (0.9%)	2
pleural effusion	1/218 (0.5%)	2	0/217 (0%)	0	0/218 (0%)	0
pulmonary hypertension	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
respiratory failure	1/218 (0.5%)	1	0/217 (0%)	0	0/218 (0%)	0
Other (Not Including Serious) Adverse Events
	SUN-101 50 mcg BID eFlow (CS) Nebulizer		SUN-101 25 mcg BID eFlow (CS) Nebulizer		Placebo BID eFlow (CS) Nebulizer
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	37/218 (17%)		23/217 (10.6%)		38/218 (17.4%)
Respiratory, thoracic and mediastinal disorders
chronic obstructive ulmonary disease	19/218 (8.7%)	19	9/217 (4.1%)	9	17/218 (7.8%)	19
cough	21/218 (9.6%)	22	16/217 (7.4%)	20	22/218 (10.1%)	23

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.