Study to Investigate the Dose Response, Safety and Efficacy of Nebulized EP-101(SUN101) in Patients With Chronic Obstructive Pulmonary Disease (COPD): GOLDEN-1 Study

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to determine steady-state efficacy and dose response profile and to assess safety and pharmacokinetic profile of nebulized EP-101(SUN101) after 7-day dosing using an investigational high efficiency nebulizer (eFlow®) compared with placebo and two active comparators in patients with moderate to severe Chronic Obstructive Pulmonary Disease (COPD).

Detailed Description
-----------------
This is a phase 2, multicenter, randomized, double-blind, placebo-controlled, four-period, incomplete block design cross-over study using EP-101(SUN101) and open-label active controls (tiotropium bromide and ipratropium bromide). The study population will consist of subjects of 40-75 years of age with moderate to severe COPD. Approximately 133 subjects diagnosed with moderate to severe COPD will be enrolled in order to achieve minimum 105 subjects completing the study. Following a run-in phase, each subject will be randomly assigned to one of 7 treatment sequences,(96 sequences when order of administration is considered), with each sequence comprised of four 7-day Treatment Periods. There will be a washout period of 7 days between each Treatment Period. Study visits will be conducted on Days 1 and 7 of each Treatment Period, with an overnight stay required in the clinic during these visits. A Final Study Visit will be conducted 7 days following the last study treatment. During each Treatment Period, study treatments will be administered once daily (QD), except for ipratropium inhalation solution, which will be administered three times daily (TID). EP-101 (SUN101)active and placebo treatments will be administered using an investigational high-efficiency eFlow® nebulizer. Tiotropium bromide (Spiriva®) will be administered in an open-label manner via Handihaler® dry-powder inhaler (DPI). Ipratropium bromide inhalation solution will be administered in an open-label manner via general purpose nebulizer. This study was previously posted by Elevation Pharmaceuticals, Inc. On September 5, 2012, Elevation was acquired by merger with Sunovion Pharmaceuticals Inc. (Sunovion), which resulted in Elevation becoming a direct wholly-owned subsidiary of Sunovion. In conjunction with this acquisition, the name of Elevation has been changed to Sunovion Respiratory Development Inc.

Official Title
-----------------
A Randomized, Double-Blind, Placebo-Controlled, Multi-Center, Seven Arm, Four-Period Cross-over, Incomplete Block Design, 7-Day Dosing Study to Assess the Dose-Response, Safety, and Efficacy of EP-101 (SUN101) in Subjects With Moderate to Severe COPD

Conditions
-----------------
Chronic Obstructive Pulmonary Disease

Intervention / Treatment
-----------------
* Drug: EP-101 via nebulizer (eFlow®) 25 ug
* Drug: EP-101 via nebulizer (eFlow®) 50 ug
* Drug: EP-101 via nebulizer (eFlow®) 100 ug
* Drug: Placebo EP-101
* Drug: Tiotropium bromide via (Spiriva® Handihaler®)
* Drug: Ipratropium bromide Inhalation Solution via Handihaler® DPI
* Drug: EP-101 via nebulizer (eFlow®) 200 ug


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 40-75 years of age Clinical diagnosis of moderate to severe COPD Current/ex-smokers with at least 10 pack-year smoking history Post-bronchodilator FEV1 ≥ 30% and ≤ 70% predicted normal values Post-bronchodilator FEV1/FVC ratio of ≤ 0.70 Post-bronchodilator improvement in FEV1 ≥ 12% and ≤ 30%, and a minimum of 100 mL Willing and able to remain at the study site for at least 24 hours at each study visit Signed written informed consent Exclusion Criteria: Current evidence or recent history of any clinically significant and unstable disease or abnormality (e.g., myocardial infarction, cardiac failure, uncontrolled hypertension, life-threatening arrhythmias, uncontrolled diabetes) Primary diagnosis of asthma History of malignancy within the past 5 years History of COPD exacerbation within 6 weeks of Screening Daily oxygen therapy > 10 hours per day Systemic steroids use within 6 weeks of Screening Respiratory tract infection within 6 weeks of Screening History of tuberculosis, bronchiectasis History of urinary retention or bladder neck obstruction type symptoms History of glaucoma Prolonged QTc interval (>460msec) or history of long QT syndrome Recent history of alcohol or drug abuse Females who are pregnant or breastfeeding, or if of child-bearing potential unwilling to practice acceptable birth control methods History of hypersensitivity or intolerance to aerosol medications Participation in another investigational drug study within 30 days of Screening

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: EP-101 via nebulizer (eFlow®) 25 ug<br>EP-101 via nebulizer (eFlow®) | Drug: EP-101 via nebulizer (eFlow®) 25 ug<br>* EP-101 (25 ug ) Dose 1 administered once daily for 7 days<br>* Other names: SUN101;|
| Active Comparator: Tiotropium bromide via (Spiriva® Handihaler®)<br>Tiotropium bromide via (Spiriva® Handihaler®) | Drug: Tiotropium bromide via (Spiriva® Handihaler®)<br>* Tiotropium 18 µg administered once daily for 7 days using Handihaler® DPI<br>* Other names: Tiotropium bromide;|
| Active Comparator: Ipratropium bromide Inhalation Solution<br>Ipratropium bromide Inhalation Solution via Handihaler® DPI | Drug: Ipratropium bromide Inhalation Solution via Handihaler® DPI<br>* Ipratropium 500 µg administered three times daily for 7 days using general purpose nebulizer<br>* Other names: Ipratropium bromide;|
| Placebo Comparator: Placebo EP-101<br>Placebo | Drug: Placebo EP-101<br>* Placebo EP-101 administered once daily for 7 days<br>* Other names: Placebo;|
| Experimental: EP-101 via nebulizer (eFlow®) 50 ug<br>EP-101 via nebulizer (eFlow®) | Drug: EP-101 via nebulizer (eFlow®) 50 ug<br>* EP-101 (50 ug ) administered once daily for 7 days<br>* Other names: SUN101;|
| Experimental: EP-101 via nebulizer (eFlow®) 100 ug<br>EP-101 via nebulizer (eFlow®) | Drug: EP-101 via nebulizer (eFlow®) 100 ug<br>* EP-101 (100ug) administered once daily for 7 days<br>* Other names: SUN101;|
| Experimental: EP-101 via nebulizer (eFlow®) 200 ug<br>EP-101 via nebulizer (eFlow®) | Drug: EP-101 via nebulizer (eFlow®) 200 ug<br>* EP-101 (200) ug administered once daily for 7 days<br>* Other names: SUN101;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in 24 Post Dose Trough Forced Expiratory Volume in 1 Second (FEV1) | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. Trough FEV1 was defined as the mean of the spirometry values collected at 23 hours 30 minutes and 24 hours post dose for Day 1 and Day 7 within each Treatment Period. Baseline was calculated as the mean of the FEV1 values at 45 minutes and 15 minutes prior to the morning dose at Day 1 of each Treatment Period. Change from baseline was calculated as the trough FEV1 value minus the baseline for Day 1 and Day 7. | Day 1 and Day 7 | 
| Standardized Change in FEV1 Area Under the Curve (AUC) (0-12hr , 12-24hr, 0-24hr) on Day 1 and Day 7 | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. The standardized FEV1 AUC(0-12hr and 12-24hr) on Day 1 and Day 7 was calculated using the trapezoidal rule from the changes in FEV1 at Day 1 and Day 7, respectively, from the baseline value (the mean of the two FEV1 values at 45 minutes and 15 minutes prior to morning dose at Day 1 of the respective Treatment Periods) and dividing by the actual length of the time interval. | Day 1 and Day 7 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Peak FEV1 (Maximum FEV1 During the First 4 Hours Post-dose on Day 1 and Day 7) | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines | Day 1 and Day 7 | 
| Treatment Responders (Number of Subjects With Clinically Meaningful Change From Pre-dose in Trough FEV1 on Day 1 and Day 7) | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. Clinically meaningful is defined as when the change from baseline (mean of the two pre-dose values at Day 1) in 24 hour trough FEV1 on a SUN-101 treatment is more than 100 mL compared to the mean change in trough FEV1 from all subjects on the placebo treatment. | Day 1 and Day 7 | 
| Number of Participants With Adverse Events, Vital Signs, and Clinically Significant Abnormal ECG Values and Laboratory Tests | AEs are defined as existing conditions which worsen or events which occur during the course of the clinical trial after treatment. Vital signs were performed during the screening period to confirm study eligibility and at the final study visit. ECGs were performed during the screening period to confirm study eligibility. Vital signs and ECG were additionally collected within 30 minutes pre-dose; and 30 minutes, and 1, 2, 4, 6, 12 hours, and 23 hours 45 minutes post-dose within each treatment period. Clinical laboratory assessments were conducted during the screening period, at each study visit during each treatment period, and at the final study visit. | Day 1 through Day 7 | 
| Rescue Medication Use | Mean number of puffs of daily rescue medication | Day 1 through Day 7 | 
| Treatment Responders (Percentage of Subjects With Clinically Meaningful Change From Pre-dose in Trough FEV1 on Day 1 and Day 7) | percentage of subjects with clinically meaningful change from pre-dose in trough FEV1 on Day 1 and Day 7 Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. | Day 1 and Day 7 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
COPD