Study to Determine the Amount of Glycopyrrolate Absorbed in the Lungs After Taking the Medicine With a eFlow Nebulizer and Seebri® Breezhaler® With and Without Activated Charcoal in Subjects With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD).

Study Overview
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Brief Summary
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The purpose of this research study is to determine the amount of medicine absorbed in the lungs following dosing via eFlow nebulizer and Seebri® Breezhaler® with and without activated charcoal in subjects with moderate to severe chronic obstructive pulmonary disease (COPD).

Detailed Description
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This is a randomized, open-label, single-dose per dosing period, five-way crossover study in subjects 40 to 70 years of age with a diagnosis of moderate to severe COPD per Global Initiative for Chronic Obstructive Lung Disease guidelines. After a subject provides consent for study participation, there will be a Screening Period lasting up to 3 weeks to determine study eligibility and to allow for appropriate washout of prohibited medications. Eligible subjects will be randomized to one of 10 treatment Sequences. There will be a minimum of a 7-day washout period between each treatment visit. At each visit, subjects will receive one dose of study medication according to the sequence assigned. Subjects with a ≥ 20% decrease in forced expiratory volume in one second (FEV1) based on review of the Visit predose value compared with the Screening value will be evaluated by the investigator for continuation in the study. Subjects taking theophylline will not be able to participate in the study.

Official Title
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A Crossover Clinical Pharmacology Study to Evaluate the Total Systemic Exposure and Lung Bioavailability of SUN-101 and Seebri® Breezhaler® Administered With and Without Activated Charcoal in Subjects With Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)

Conditions
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COPD

Intervention / Treatment
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* Drug: SUN-101 via eFlow nebulizer
* Drug: SUN-101 via eFlow nebulizer with activated charcoal
* Drug: Seebri® Breezhaler®
* Drug: Seebri® Breezhaler® with activated charcoal
* Drug: Glycopyrrolate Injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female patients 40 to 70 years-old, inclusive. A clinical diagnosis of moderate to severe 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 ≥ 30% and ≤ 80% of predicted normal during the Screening Period. Post-bronchodilator (following inhalation of ipratropium bromide) FEV1/FVC ratio ≤ 0.70 during the Screening Period. Ability to perform reproducible spirometry according to the American Thoracic Society (ATS) and/or European Respiratory Society (ERS) guidelines (2005). Subject, if female ≤ 70 years of age and of child bearing potential, must have a negative urine 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 remain at the study site for at least 24 hours for each treatment day. 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, included but not limited to the following: Unstable ischemic heart disease (diagnosis of myocardial infarction or admission for acute coronary syndrome) within 6 months of screening. Unstable cardiac arrhythmia or heart failure (change in treatment plan) within 6 months. Treatment for diabetes mellitus within 6 months of screening. Current evidence or history of a clinically significant abnormality of cardiac rhythm and/or conduction findings. Concomitant clinically significant respiratory disease other than COPD (eg, asthma, tuberculosis, bronchiectasis, or other non-specific pulmonary disease). 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. Recent history of COPD exacerbation requiring hospitalization or need for increased treatments for COPD within 6 weeks prior to the Screening Period. Use of daily oxygen therapy > 10 hours per day. Use of oral, intravenous, or intramuscular steroids within 3 months prior to the Screening Period. Respiratory tract infection within 6 weeks prior to or during the Screening Period. Significant blood loss (> 500 mL) or donated blood within 60 days preceding screening or plans to donate blood within 60 days after completing the study. History of or clinically significant ongoing bladder outflow obstruction or history of catheterization for relief of bladder outflow obstruction within the previous 6 months. History of narrow-angle glaucoma. Prolonged QTc interval (> 450 msec for males and > 470 msec for females) during the Screening Period, or history of long QT syndrome. Recent documented history (previous 12 months) of substance abuse. .Positive urine drug screen at Visit 1 provided the subject is unable to produce a valid medical rationale for the test result (eg, prescription medication). Positive HbsAg, Hepatitis C antibody, or HIV 1/2 antibody test at Screening. History of hypersensitivity or intolerance to aerosol medications, β2-agonists, anticholinergics, or sympathomimetic amines. 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 the Screening Period, or current participation in another investigational drug trial in which study treatment is being administered, including a SUN-101 study Previously received SUN-101 (active treatment; formerly known as EP-101). Previously received any glycopyrrolate product within 28 days of Screening. Subject is taking theophylline.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 70 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: SUN-101 via eFlow nebulizer<br>50 mcg glycopyrrolate via Electronic Nebulizer | Drug: SUN-101 via eFlow nebulizer<br>* 50 mcg glycopyrrolate via Electronic Nebulizer<br>* Other names: Glycopyrrolate;|
| Experimental: SUN-101 via eFlow nebulizer with activated charcoal<br>50 mcg glycopyrrolate via Electronic Nebulizer with activated charcoal | Drug: SUN-101 via eFlow nebulizer with activated charcoal<br>* 50 mcg glycopyrrolate via Electronic Nebulizer with activated charcoal<br>* Other names: Glycopyrrolate;|
| Active Comparator: Seebri® Breezhaler®<br>63 mcg glycopyrronium bromide (50 mcg glycopyrronium) via DPI | Drug: Seebri® Breezhaler®<br>* 63 mcg glycopyrronium bromide (50 mcg glycopyrronium) via DPI<br>* Other names: glycopyrronium, glycopyrronium bromide;|
| Active Comparator: Seebri® Breezhaler® with activated charcoal<br>: : 63 mcg glycopyrronium bromide (50 mcg glycopyrronium) via DPI with activated charcoal | Drug: Seebri® Breezhaler® with activated charcoal<br>* 63 mcg glycopyrronium bromide (50 mcg glycopyrronium) via DPI with activated charcoal<br>* Other names: glycopyrronium, glycopyrronium bromide;|
| Active Comparator: : Glycopyrrolate Injection<br>50 mcg glycopyrrolate via IV infusion | Drug: Glycopyrrolate Injection<br>* 50 mcg glycopyrrolate via IV<br>* Other names: Glycopyrrolate;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax | maximum observed concentration-Cmax is calculated from plasma concentrations analyzed from blood samples collected between 0 and 48 hr. | Up to Week 5 | 
| Area Under the Curve From Time Zero to 24 Hours (AUC0_24) | Area under the drug concentration-time curve from time zero to 24 hours postdose pk parameteres are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr | Up to Week 5 | 
| Area Under the Curve From Time Zero to Infinity (AUC0_infinity) | calculated by summing AUC0-last and the AUC extrapolated from tlast to infinity: AUC0-∞ = AUC0-last+ Clast / | λz | Clast / | λz | is the extrapolated area under the curve from tlast to infinity. If this quantity is greater than 20% of AUC0-∞, then AUC0-∞ was considered to be missing. Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. | Up to Week 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clearance (CL) for IV Infusion of 50 mcg of Glycopyrrolate | calculated as Dose/AUC0-inf after the IV dose administration. If AUC0-inf is missing, then CL was considered as missing. Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. | Up to Week 5 | 
| Volume of Distribution During the Elimination Phase (Vz) for IV Infusion of 50 mcg of Glycopyrrolate | calculated as Dose/(AUC0-inf*λz). Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. | Up to Week 5 | 
| Time of Occurrence of Cmax (Tmax) for IV Infusion of 50 mcg of Glycopyrrolate | The time 0 is based on start of the infusion. Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. | Up to Week 5 | 
| Terminal Half Life (t1/2) for IV Infusion of 50 mcg of Glycopyrrolate | calculated as ln(2) / λz . At least 3 data points at the terminal elimination phase were required to determine t½. Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. | Up to Week 5 | 
| Area Under the Curve Zero to 48 Hours (AUC0_48) for Seebri Breezhaler and Sun-101 AUC0-48, CL/F, Vz/F, Tmax, t½, and Dose Normalized Cmax, AUC0-24, AUC0-48, AUC0-∞ - AUC0-∞ - | Area under the drug concentration-time curve from time zero to 48 hours postdose Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. | Up to Week 5 | 
| Apparent Clearance Calculated as Dose/AUC0-INF After Extravascular Dose Administration of Seebri Breezhaler and SUN-101 | calculated as Dose/AUC0-∞ after extravascular dose administration, where F = Bioavailability. If AUC0-∞ is missing, then CL/F is considered as missing. Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. | up to week 5 | 
| Apparent Volume of Distribution (Vz/F) After Extravascular Dose Administration of Seebri Breezhaler and SUN-101 | calculated as Dose/(AUC0-∞* λz), where F = Bioavailability. If AUC0-∞ is missing, then Vz/F is considered as missing. Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr | up to week 5 | 
| Time of Occurrence of Cmax (Tmax) for Seebri Breezhaler and SUN-101 | The time 0 is based on start of the inhalation. Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. | up to week 5 | 
| Terminal Half Life (t1/2) for for Seebri Breezhaler and SUN-101 | calculated as ln(2) / λz . At least 3 data points at the terminal elimination phase were required to determine t½. Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. | up to week 5 | 
| Dose Normalized Cmax for Seebri and SUN-101. | Maximum observed concentration multiplied by the dose normalization factor. Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. The dose normalization factor calculation has two components: dose equivalent glycopyrrolate amount and the delivery efficiency (% dose delivered). For Sun-101 50 mcg, the dose normalization factor is 1.59, for Seebri Breezhaler it is 0.9. | up to week 5 | 
| Dose Normalized Area Under the Curve Zero to 24 Hours (AUC0_24) for Seebri and SUN-101 | Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. Area under the drug concentration-time curve from time zero to 24 hours postdose multiplied by the dose normalization factor. The dose normalization factor calculation has two components: dose equivalent glycopyrrolate amount and the delivery efficiency (% dose delivered). For Sun-101 50 mcg, the dose normalization factor is 1.59, for Seebri Breezhaler it is 0.9. | up to week 5 | 
| Dose Normalized Area Under the Curve Zero to 48 Hours (AUC0_48) for Seebri and SUN-101 | Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. Area under the drug concentration-time curve from time zero to 48 hours postdose multiplied by the dose normalization factor. The dose normalization factor calculation has two components: dose equivalent glycopyrrolate amount and the delivery efficiency (% dose delivered). For Sun-101 50 mcg, the dose normalization factor is 1.59, for Seebri Breezhaler it is 0.9. | up to week 5 | 
| Dose Normalized Area Under the Curve Zero From Zero to Infinity (AUC0_inf) for Seebri and SUN-101 | Pk parameters are calculated from plasma concentration analyzed from blood samples collected between 0 and 48 hr. Area under the drug concentration-time curve from zero to infinity, calculated by summing AUC0-last and the AUC extrapolated from tlast to infinity multiplied by the dose normalization factor: dose normalization factor* (AUC0-∞ = AUC0-last+ Clast / | λz | ) Clast / | λz | is the extrapolated area under the curve from tlast to infinity. If this quantity is greater than 20% of AUC0-∞, then AUC0-∞ was considered to be missing. The dose normalization factor calculation has two components: dose equivalent glycopyrrolate amount and the delivery efficiency (% dose delivered). For Sun-101 50mcg , the dose normalization factor is 1.59, for Seebri Breezhaler it is 0.9. | up to week 5 | 
| The Number of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation | An adverse event (AE) that occurred on or after the first dose of study medication, any AE with a missing start date and a stop date on or after the first dose of study medication, or any AE with both a missing start and stop date. | Up to Week 5 | 
| The Percentage of Subjects With Adverse Events (AEs), Serious Adverse Events (SAEs), and AEs Leading to Discontinuation | An adverse event (AE) that occurred on or after the first dose of study medication, any AE with a missing start date and a stop date on or after the first dose of study medication, or any AE with both a missing start and stop date. | Up to Week 5 | 

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