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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter, Efficacy and Safety Trial of 12 Weeks of Treatment With Nebulized SUN-101 in Patients With COPD: GOLDEN-4 (Glycopyrrolate for Obstructive Lung Disease Via Electronic Nebulizer

Conditions
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COPD, Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: SUN-101 50 mcg BID eFlow (CS) nebulizer
* Drug: SUN-101 25 mcg BID eFlow (CS) nebulizer
* Drug: Placebo eFlow (CS) nebulizer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients age ≥ 40 years, inclusive A clinical diagnosis of COPD according to the GOLD 2014 guidelines Current smokers or ex-smokers with at least 10 pack-year smoking history (eg, at least 1 pack/day for 10 years, or equivalent) Post-bronchodilator (following inhalation of ipratropium bromide) FEV1 < 80% of predicted normal and > 0.7 L during Screening (Visit 1) Post-bronchodilator (following inhalation of ipratropium bromide) FEV1/FVC ratio < 0.70 during Screening (Visit 1) Ability to perform reproducible spirometry according to the American Thoracic Society (ATS) and European Respiratory Society (ERS) guidelines (2005) 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 Willing and able to provide written informed consent Willing and able to attend all study visits and adhere to all study assessments and procedures Exclusion Criteria: 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 Concomitant clinically significant respiratory disease other than COPD (eg, asthma, tuberculosis, bronchiectasis or other non-specific pulmonary disease). Recent history of COPD exacerbation requiring hospitalization or need for increased treatments for COPD within 6 weeks prior to Screening (Visit 1). Use of daily oxygen therapy > 12 hours per day Respiratory tract infection within 6 weeks prior to Screening (Visit 1) Use of oral, intravenous, or intramuscular steroids within 3 months prior to Screening (Visit 1) 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 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 History of or clinically significant on-going bladder outflow obstruction or history of catheterization for relief of bladder outflow obstruction within the previous 6 months History of narrow angle glaucoma History of hypersensitivity or intolerance to aerosol medications Recent documented history (within the previous 3 months) of substance abuse Significant psychiatric disease that would likely result in the subject not being able to complete the study, in the opinion of the Investigator 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 Previously received SUN-101 (active treatment; formerly known as EP-101) Contraindicated for treatment with, or having a history of reactions/hypersensitivity to anticholinergic agents, beta2 agonists, or sympathomimetic amines

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

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

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

Secondary Outcome Measures

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

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chronic Obstructive Pulmonary Disease, COPD