Assessment of the Safety and Ability of a Once-a-day Dose of an Orally Inhaled Medicine [i.e., Glycopyrrolate Inhalation Solution = GIS] to Improve Airflow in the Lungs When Delivered Using an eFlow Nebulizer in Patients With Chronic Obstructive Pulmonary Disease (COPD)

Study Overview
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Brief Summary
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The study assessed the safety and ability of an orally inhaled medicine [i.e., Glycopyrrolate Inhalation Solution = GIS] to improve airflow in the lungs when delivered using an eFlow nebulizer in 42 patients with Chronic Obstructive Pulmonary Disease (COPD). Each patient randomly received several, single doses of GIS, or placebo, separated by approximately 1 to 2 weeks. After the dose was given, lung airflow was measured over 24 hours and blood was collected to measure how much GIS was in the bloodstream. The study was conducted to find the once-a- day GIS dose that produced the highest improvement in lung airflow using the eFlow nebulizer.

Official Title
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Randomized, Placebo-Controlled, Double-Blind, Dose Ranging, Single-Dose, 6-Way Crossover Study to Assess Safety, Efficacy and Pharmacokinetics of EP-101 Using eFlow Nebuliser in Patients With COPD

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Glycopyrrolate Inhalation Solution12.5μg
* Drug: Glycopyrrolate Inhalation Solution 50μg
* Drug: Glycopyrrolate Inhalation Solution 100μg
* Drug: Glycopyrrolate Inhalation Solution 200μg
* Drug: Glycopyrrolate Inhalation Solution 400μg
* Drug: Placebo 0.5mL


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female patients aged 40 through 75 years, inclusive A clinical diagnosis of COPD according to the GOLD guidelines Current smokers or ex-smokers with at least 10 pack-year smoking history (e.g., at least 1 pack/day for 10 Post-bronchodilator FEV1 30-70% of predicted normal at the Screening Visit Post-bronchodilator FEV1/FVC ratio < 0.70 at the Screening Visit Improvement in FEV1 >12% and 150 mL following inhalation of ipratropium bromide at the Screening Visit Ability to perform reproducible spirometry according to the ATS/ERS guidelines Willing to stay at the study site for approximately 30 hours on each treatment visit Willing and able to provide written informed consent Exclusion Criteria: Females who are pregnant or lactating at the Screening Visit, or if of childbearing potential not using one of the following acceptable means of birth control throughout the study: Abstinence Post-menopausal for at least two years Surgically sterile (i.e., tubal ligation, hysterectomy) Oral contraceptives (taken for at least one month prior to the Screening Visit) Approved implantable or injectable contraceptives (e.g., Norplant®, Depo-Provera® or equivalent) Barrier methods (e.g., condoms with spermicide) Intrauterine device (i.e., IUD) Vasectomy of male partner Non-heterosexual life style Current evidence or recent history of any clinically significant disease (other than COPD) or abnormality in the opinion of the Investigator that would put the subject at risk or which would compromise the quality of the study data; including but not limited to cardiovascular disease, myocardial infarction, cardiac failure, uncontrolled hypertension, life-threatening arrhythmias, uncontrolled diabetes, neurologic or neuromuscular disease, liver disease, gastrointestinal disease or electrolyte abnormalities Recent history of hospitalization due to an exacerbation of airway disease within 3 months or need for increased treatments for COPD within 6 weeks prior to the Screening Visit Primary diagnosis of asthma Prior lung volume reduction surgery or history of chest/lung irradiation Regular use of daily oxygen therapy Use of systemic (eg, intramuscular or intravenous) steroids within 3 months prior to the Screening Visit Respiratory tract infection within 6 weeks prior to the Screening Visit History of tuberculosis, bronchiectasis or other non- specific pulmonary disease History of urinary retention or bladder neck obstruction type symptoms History of narrow-angle glaucoma Clinically significant abnormal ECG Positive Hepatitis B surface antigen or positive Hepatitis C antibody Positive screening test for HIV antibodies Current or recent history (previous 12 months) of excessive use or abuse of alcohol Current evidence or history of abusing legal drugs or use of illegal drugs or substances Donation of 450 mL of blood within 8 weeks of the Screening Visit History of hypersensitivity or intolerance to aerosol medications Participation in another investigational drug study was received within 30 days prior to the Screening Visit

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


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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glycopyrrolate Inhalation Solution12.5μg<br>Glycopyrrolate Inhalation Solution12.5μg via e-flow nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution12.5μg<br>* Glycopyrrolate Inhalation Solution12.5μg via eFlow, once daily<br>* Other names: GIS;|
| Experimental: Glycopyrrolate Inhalation Solution 50μg<br>Glycopyrrolate Inhalation Solution 50mg via e-flow nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution 50μg<br>* Glycopyrrolate Inhalation Solution 50μg via eFlow, once daily<br>* Other names: GIS;|
| Experimental: Glycopyrrolate Inhalation Solution 100μg<br>Glycopyrrolate Inhalation Solution 100μg via e-flow nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution 100μg<br>* Glycopyrrolate Inhalation Solution 100μg via eFlow, once daily<br>* Other names: GIS;|
| Experimental: Glycopyrrolate Inhalation Solution 200μg<br>Glycopyrrolate Inhalation Solution 200μg via e-flow nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution 200μg<br>* Glycopyrrolate Inhalation Solution 200μg via eFlow, once daily<br>* Other names: GIS;|
| Experimental: Glycopyrrolate Inhalation Solution 400μg<br>Glycopyrrolate Inhalation Solution 400μg via e-flow nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution 400μg<br>* Glycopyrrolate Inhalation Solution 400μg via eFlow, once daily<br>* Other names: GIS;|
| Placebo Comparator: Placebo 0.5mL<br>Placebo 0.5mL via e-flow nebulizer, once daily | Drug: Placebo 0.5mL<br>* Placebo 0.5mL via eFlow, once daily<br>* Other names: Placebo;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Trough FEV1 (Change From Baseline) | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. Trough FEV1 was defined as the mean of FEV1 values obtained at 23 hours 30 minutes and 24 hours post-dose of each Treatment Visit. | 24hr post dose | 
| Standardized FEV1AUC0-12 Area Under the FEV1 Curve From 0 to 12 Hours Post-dose ( Actual and Change From Baseline). | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines.. The standardized actual FEV1 AUC(0-12) was calculated using the trapezoidal rule divided by the actual hours from the first FEV1 to the last FEV1 in the interval. Standardized change from baseline FEV1 AUC(0-12) was also calculated similarly, using the change from pre-dose FEV1. | 0-12h post dose | 
| Standardized FEV1AUC12-24 Area Under the FEV1 Curve From 12 to 24 Hours Post- Dose (Actual and Change From Baseline). | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. The standardized actual FEV1 AUC(12-24) was calculated using the trapezoidal rule divided by the actual hours from the first FEV1 to the last FEV1 in the interval. Standardized change from baseline FEV1 AUC(12-24) was also calculated similarly, using the change from pre-dose FEV1. | 12-24h post dose | 
| Standardized FEV1 AUC0-24 Area Under the FEV1 Curve From 0 to 24 Hours Post-dose (Actual and Change Baseline) | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. . The standardized actual FEV1 AUC(0-24) was calculated using the trapezoidal rule divided by the actual hours from the first FEV1 to the last FEV1 in the interval. Standardized change from baseline FEV1 AUC(0-24) was also calculated similarly, using the change from pre-dose FEV1. | 0 to 24h | 
| Peak FEV1 (Change From Baseline and Percent Change) | spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. . The peak FEV1 was defined as the highest post-dose FEV1 value within 4 hrs after the dose. Percent change from baseline was calculated as 100 times the difference of peak FEV1 minus baseline FEV1 divided by baseline FEV1. | 0-4h post dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cmax; Maximum Observed Plasma Concentration | Pk parameters are calculated from glycopyrrolate plasma concentration analysed from serial blood samples collected between 0 and 12 hr | 0 to 12 hour | 
| Tmax; Time to Maximum Observed Plasma Concentration | Pk parameters are calculated from glycopyrrolate plasma concentration analysed from serial blood samples collected between 0 and 12 hr | 0 to 12 hours | 
| t1/2; Plasma Half-life | Pk parameters are calculated from glycopyrrolate plasma concentration analysed from serial blood samples collected between 0 and 12 hr | 0 to 12 hour | 
| AUC0-t; Area Under the Plasma Concentration-time Curve From Time Zero to Time of Last Measurable Drug Concentration. | Pk parameters are calculated from glycopyrrolate plasma concentration analysed from serial blood samples collected between 0 and 12 hr | 0 to 12 hour | 
| AUC0-inf Area Under the Plasma Concentration-time Curve From Time Zero to Infinity | Pk parameters are calculated from glycopyrrolate plasma concentration analysed from serial blood samples collected between 0 and 12 hr | 0 to 12 hour | 
| Number of Subjects Who Died, Number of Subjects With Treatment Emergent SAEs, Number of Subjects Who Discontinued Due to AE | AE's are defined as existing conditions which worsen or events which occur during the course of the clinical trial after treatment | Day 69 (includes dosing Day 1, washout Day 12, safety follow up Day 69) | 
| Number of Subjects With Clinically Significant Abnormal Vital Signs Reported During the Study | Vital signs were measured at screening and at each Treatment Visit pre-dose (within 30 minutes prior to dose); post-dose at 30 minutes and 1, 2, 4, 8, 12 and 24 hours; and then at the post study assessment. | 0-24 h | 
| Number of Clinically Significant Abnormal Laboratory Results Reported During the Study | Clinical safety lab parameters were collected at screening and at the post study assessment. Any laboratory values that were out of range of normal reference values were evaluated by the Investigators. | Day -14, Day 69 | 
| Number of Subjects With Clinically Significant ECG Parameters Reported During the Study | ECGs were recorded at screening and at each study treatment visit pre-dose (within 30 minutes prior to dose); post-dose at 30 minutes and 1, 2, 4, 8, 12 and 24 hours; and then at the post study assessment. | 0 to 24h | 
| Percentage of Subjects With Treatment Emergent AEs | AE's are defined as existing conditions which worsen or events which occur during the course of the clinical trial after treatment | Day 69 (includes dosing Day 1, washout Day 12, safety follow up Day 69) | 

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