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

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)

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.

Study Overview

• Status: Completed
• Conditions: COPD
• Intervention / Treatment: 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

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 Type: Interventional
• Enrollment (Actual): 653
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Anniston, Alabama, United States, 36207
      • Pinnacle Research Group, LLC
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • Pulmonary Associates, PA
    • Tempe, Arizona, United States, 85283
      • Clinical Research Consortium - Arizona
    • Tucson, Arizona, United States, 85710
      • Desert Sun Clinical Research, LLC
  • Colorado
    • Wheat Ridge, Colorado, United States, 80033
      • Western States Clinical Research, Inc.
  • Florida
    • Clearwater, Florida, United States, 33765
      • Clinical Research of West Florida, Inc.
    • Clermont, Florida, United States, 34711
      • Clermont Medical Research
    • Edgewater, Florida, United States, 32132
      • Riverside Clinical Research
    • Kissimmee, Florida, United States, 34741
      • Pulmonary Disease Specialists, PA, d/b/a PDS Research
    • Miami, Florida, United States, 33155
      • AppleMed Research, Inc.
    • Miami, Florida, United States, 33186
      • Clinical Trials of Florida, LLC
    • Orlando, Florida, United States, 32825
      • Florida Institute for Clinical Research, LLC
    • Panama City, Florida, United States, 32405
      • Emerald Coast Research Associates
    • Tampa, Florida, United States, 33603
      • Clinical Research of West Florida, Inc
  • Kentucky
    • Fort Mitchell, Kentucky, United States, 41017
      • Abraham Reasearch, PLLC
  • Michigan
    • Livonia, Michigan, United States, 48152
      • Pulmonary Research Institute of Southeast Michigan
  • Minnesota
    • Edina, Minnesota, United States, 55435
      • Minnesota Lung Center
    • Woodbury, Minnesota, United States, 55125
      • Minnesota Lung Center
  • Missouri
    • Saint Charles, Missouri, United States, 63301
      • Midwest Chest Consultants, P.C.
  • Nevada
    • Las Vegas, Nevada, United States, 89119
      • Clinical Research Consortium
  • New York
    • Rochester, New York, United States, 14618
      • AAIR Research Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • American Health Research, Inc.
    • Hickory, North Carolina, United States, 28602
      • Hickory Research Center
    • Raleigh, North Carolina, United States, 27607
      • North Carolina Clinical Research
    • Wilmington, North Carolina, United States, 28401
      • PMG Research of Wilmington
  • Ohio
    • Columbus, Ohio, United States, 43235
      • Optimed Research, LTD
    • Columbus, Ohio, United States, 31904
      • Columbus Regional Research Institute
    • Columbus, Ohio, United States, 43213
      • Columbus Clinical Research, Inc
  • Oregon
    • Medford, Oregon, United States, 97504
      • Clinical Research Institute of Southern Oregon, PC
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15243
      • Research Protocol Management Specialists
  • Rhode Island
    • East Providence, Rhode Island, United States, 02914
      • Safe Harbor Clinical Research
  • South Carolina
    • Easley, South Carolina, United States, 29640
      • Palmetto Medical Research Associates, LLC
    • Greenville, South Carolina, United States, 29615
      • Upstate Pharmaceutical Research
    • Greenville, South Carolina, United States, 29615
      • Greenville Pharmaceutical Research, Inc
    • Indian Land, South Carolina, United States, 29707
      • Piedmont Research Partners, LLC
    • Spartanburg, South Carolina, United States, 29303
      • S. Carolina Pharmaceutical Research
    • Spartanburg, South Carolina, United States, 29303
      • Spartanburg Medical Research
    • Union, South Carolina, United States, 29379
      • CU Pharmaceutical Research
  • Texas
    • Fort Worth, Texas, United States, 76104
      • Texas Pulmonary and Critical Care Consultants, PA
    • Houston, Texas, United States, 77099
      • Pioneer Research Solutions, Inc.
    • New Braunfels, Texas, United States, 78130
      • Central Texas Health Research
    • San Antonio, Texas, United States, 78229
      • Sylvana Research Associates
  • Virginia
    • Abingdon, Virginia, United States, 24210
      • Pulmonary Research of Abingdon, LLC
    • Richmond, Virginia, United States, 23225
      • Pulmonary Associates of Richmond, Inc.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 40 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: QUADRUPLE

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) at 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	Baseline and Week 12
Change From Baseline in Trough Forced Expiratory Volume in 1 Second (FEV1) 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).	Baseline and Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Standardized Change From Baseline at Week 12 in FEV1 Area Under the Curve (AUC) (0-12) in the Substudy Population	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).	Baseline and Week 12
Standardized Change From Baseline at Week 12 in FEV1 Area Under the Curve (AUC) (0-12) in Substudy Population	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).	Baseline and Week 12
Change From Baseline in Trough Forced Vital Capacity (FVC) at 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	Baseline and Week 12
Change From Baseline in Trough Forced Vital Capacity (FVC) 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).	Baseline and Week 12
Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) at Week 12/End of Study	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).	Baseline and Week 12
Change From Baseline in Health Status Measured by St. George's Respiratory Questionnaire (SGRQ) Week 12/End of Study	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).	Baseline and Week 12
Change in Number of Rescue Medication Puffs Per Day Over the 12-week Double-blind Treatment Period	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).	Week 0-12
Number of Subjects With Major Adverse Cardiac Events (MACE)	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)	Week 0-12
Percentage of Subjects With Major Cardiac Events (MACE)	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)	Week 0-12
Number of Subjects With Treatment Emergent Adverse Events (TEAE)	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.	Week 0-12
Percent of Subjects With Treatment Emergent Adverse Events (TEAE)	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.	Week 0-12
Number of Subjects With Treatment Emergent Serious Adverse Events (SAE)	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	Week 0-12
Percent of Subjects With Treatment Emergent Serious Adverse Events (SAE)	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	Week 0-12
Number of Subjects Who Discontinue Treatment Due to TEAE	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.	Week 0-12
Percent of Subjects Who Discontinue Treatment Due to TEAE	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.	Week 0-12
Incidence Rate Per 100 Person-years of Subjects With Treatment Emergent Adverse Events (TEAE)	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.	Week 0-12

Collaborators and Investigators

• Sponsor: Sunovion Respiratory Development Inc.
• Investigators: Study Director: Respiratory Medical Director, MD, Sunovion Respiratory Director

Publications and helpful links

General Publications

• Kerwin E, Donohue JF, Goodin T, Tosiello R, Wheeler A, Ferguson GT. Efficacy and safety of glycopyrrolate/eFlow(R) CS (nebulized glycopyrrolate) in moderate-to-very-severe COPD: Results from the glycopyrrolate for obstructive lung disease via electronic nebulizer (GOLDEN) 3 and 4 randomized controlled trials. Respir Med. 2017 Nov;132:238-250. doi: 10.1016/j.rmed.2017.07.011. Epub 2017 Jul 19.
• Ohar J, Tosiello R, Goodin T, Sanjar S. Efficacy and safety of a novel, nebulized glycopyrrolate for the treatment of COPD: effect of baseline disease severity and age; pooled analysis of GOLDEN 3 and GOLDEN 4. Int J Chron Obstruct Pulmon Dis. 2018 Dec 18;14:27-37. doi: 10.2147/COPD.S184808. eCollection 2019.
• Ferguson GT, Kerwin EM, Donohue JF, Ganapathy V, Tosiello RL, Bollu VK, Rajagopalan K. Health-Related Quality of Life Improvements in Moderate to Very Severe Chronic Obstructive Pulmonary Disease Patients on Nebulized Glycopyrrolate: Evidence from the GOLDEN Studies. Chronic Obstr Pulm Dis. 2018 Jun 6;5(3):193-207. doi: 10.15326/jcopdf.5.3.2017.0178.

Study record dates

Study Major Dates

• Study Start: February 1, 2015
• Primary Completion (ACTUAL): November 1, 2015
• Study Completion (ACTUAL): November 1, 2015

Study Registration Dates

• First Submitted: January 21, 2015
• First Submitted That Met QC Criteria: January 26, 2015
• First Posted (ESTIMATE): January 27, 2015

Study Record Updates

• Last Update Posted (ACTUAL): March 22, 2018
• Last Update Submitted That Met QC Criteria: February 22, 2018
• Last Verified: February 1, 2018

More Information

Terms related to this study

• Keywords: Chronic Obstructive Pulmonary Disease
• Other Study ID Numbers: SUN101-301