Assessment of the Safety and Ability of a Once-a-day Dose of an Orally Inhaled Medicine [ie, Glycopyrrolate Inhalation Solution = GIS] to Improve Airflow in the Lungs When Delivered With an Electronic eFlow Nebulizer System 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 several doses of an orally inhaled medicine [ie, Glycopyrrolate Inhalation Solution = GIS] to improve airflow in the lungs when delivered with an electronic eFlow nebulizer system in patients with Chronic Obstructive Pulmonary Disease (COPD). The study was conducted in 12 patients in 2 parts. Part 1 was designed to find the once-a- day GIS dose that produced the highest improvement in lung airflow. Part 2 tested the GIS dose with the highest improvement in lung airflow and a placebo (ie, no drug) delivered by a general purpose nebulizer. The airflow improvements of the same GIS dose were compared between the two nebulizer systems to determine what effect the device had on GIS delivery.

Detailed Description
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In Part I, 12 subjects were randomly allocated to one of 2 cohorts, running in parallel. The 6 cohort 1 subjects received 25 mg and then 200 mg during their treatment periods 1 and 2, respectively. The 6 cohort 2 subjects received 75mg, 500mg, and 1000 mg during their treatment periods 1, 2, and 3, respectively. During Part II of the study, the same 12 subjects from Part I were randomized to receive either 200 mg jet or placebo in a 1:1 ratio.

Official Title
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Single-dose, Dose Escalation Study to Assess the Safety, Tolerability, Pharmacokinetics and Bronchodilatory Effects of Glycopyrrolate Inhalation Solution (GIS) Using a High Efficiency Nebulizer in Patients With COPD

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: Glycopyrrolate Inhalation Solution 25mg
* Drug: Glycopyrrolate Inhalation Solution 75mg
* Drug: Glycopyrrolate Inhalation Solution 200mg
* Drug: Glycopyrrolate Inhalation Solution 200mg Jet
* Drug: Glycopyrrolate Inhalation Solution 500mg
* Drug: Glycopyrrolate Inhalation Solution1000mg
* Drug: Placebo


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 years, or 10 packs/day for 1 year) Post-bronchodilator FEV1 40-80% of predicted normal Post-bronchodilator FEV1/FVC ratio < 0.70 Improvement in FEV1 >12% (minimum 150 mL) following inhalation of ipratropium bromide Ability to perform reproducible spirometry according to the ATS/ERS guidelines If female and of childbearing potential, must have had a negative pregnancy test and was not lactating at the Screening Visit, and was using one of the following acceptable means of birth control throughout the study: Post-menopausal for at least two years Surgically sterile 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 Willing and able to provide written informed consent Exclusion Criteria: 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 patients at risk or which would compromise the quality of the study data; including but not limited to cardiovascular disease, myocardial infraction, hypertension, arrhythmia, diabetes, neurological or neuromuscular disease, liver disease, gastrointestinal disease or electrolyte abnormalities. Recent history of an exacerbation of airway disease within 3 months or need for increased treatments for COPD within 6 weeks prior to the Screening Visit. Regular use of daily oxygen therapy. Use of systemic (e.g., 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 Current or recent history (previous 12 months) of excessive use or abuse of alcohol Current evidence or history of abusing legal drugs or the use of illegal drugs or substances History of hypersensitivity or intolerance to aerosol medications Participation in another investigational drug study where drug 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

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Glycopyrrolate Inhalation Solution 25mg<br>Glycopyrrolate Inhalation Solution 25 μg via eFlow nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution 25mg<br>* 25 μg oral inhalation via eFlow Nebulizer, once daily<br>* Other names: GIS;|
| Experimental: Glycopyrrolate Inhalation Solution 75mg<br>Glycopyrrolate Inhalation Solution 75 μg via eFlow nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution 75mg<br>* 75 μg oral inhalation via eFlow Nebulizer, once daily<br>* Other names: GIS;|
| Experimental: Glycopyrrolate Inhalation Solution 200mg<br>Glycopyrrolate Inhalation Solution 200 μg via eFlow nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution 200mg<br>* 200 μg oral inhalation via eFlow Nebulizer, once daily<br>* Other names: GIS;|
| Experimental: Glycopyrrolate Inhalation Solution 200mg Jet<br>Glycopyrrolate Inhalation Solution 200 μg via jet nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution 200mg Jet<br>* 200 μg oral inhalation via inhalation via jet nebulizer, once daily<br>* Other names: GIS;|
| Experimental: Glycopyrrolate Inhalation Solution 500mg<br>Glycopyrrolate Inhalation Solution 500 μg via eFlow nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution 500mg<br>* 500 μg oral inhalation via eFlow nebulizer, once daily<br>* Other names: GIS;|
| Experimental: Glycopyrrolate Inhalation Solution1000mg<br>Glycopyrrolate Inhalation Solution 1000 μg via eFlow nebulizer, once daily | Drug: Glycopyrrolate Inhalation Solution1000mg<br>* 1000 μg oral inhalation via eFlow nebulizer, once daily<br>* Other names: GIS;|
| Placebo Comparator: Placebo 0.5 mL<br>Placebo 0.5 mL via jet nebulizer, once daily | Drug: Placebo<br>* Placebo 0.5 mL oral inhalation via jet nebulizer, once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects Who Died |  | 0-47 days | 
| Number of Subjects With Treatment Emergent SAEs | AEs are defined as existing conditions which worsen or events which occur during the course of the clinical trial after treatment.AEs are defined as existing conditions which worsen or events which occur during the course of the clinical trial after treatment. SAEs are AEs that result in the following outcomes: death, are life-threatening, persistent or significant disability/incapacity, congenital anomaly/birth defect, or important medical events that may have been considered a SAE when, based upon appropriate medical judgment, they may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definition. | 0-47 days | 
| Number of Subjects Who Discontinued Due to AE | AEs are defined as existing conditions which worsen or events which occur during the course of the clinical trial after treatment. | 0-47 days | 
| Percentage of Subjects With Treatment Emergent AEs | AEs are defined as existing conditions which worsen or events which occur during the course of the clinical trial after treatment. | 0-47 days | 
| Number of Subjects With Clinically Significant Abnormal Vital Signs Reported During the Study | Vital signs were measured at screening, during the study (pre-dose, and 30 and 60 minutes and 2, 4, 8, 12, 24 and 30 hours post-dose) and at post study assessment. The clinical significance of each out of normal range vital sign parameter was determined by the investigator during the study. | 30 hrs post dose | 
| Number of Subjects With Clinically Significant Abnormal Laboratory Results Reported During the Study | Clinical safety lab parameters were collected at screening and at the post study follow-up assessment. The clinical significance of each out of normal range laboratory parameter was determined by the investigator during the study. | day 47 (post studyfollow-up assessment) | 
| Number of Subjects With Clinically Significant ECG Parameters Reported During the Study | ECGs were measured at screening, during the study (pre-dose, and 30 and 60 minutes and 2, 4, 8, 12, 24 and 30 hours post-dose) and at post study follow-up assessment. | 30hr post dose | 
| Number of Subjects With Clinically Significant Abnormal Laboratory Results Reported During the Study | Clinical safety lab parameters were collected at screening and at the post study follow-up assessment. The clinical significance of each out of normal range laboratory parameter was determined by the investigator during the study. | post study follow-up assessment (Day 47) | 
| Number of Subjects With Treatment Emergent AEs | AEs are defined as existing conditions which worsen or events which occur during the course of the clinical trial after treatment. SAEs are AEs that result in the following outcomes: death, are life-threatening, persistent or significant disability/incapacity, congenital anomaly/birth defect, or important medical events that may have been considered a SAE when, based upon appropriate medical judgment, they may have jeopardized the subject and may have required medical or surgical intervention to prevent one of the outcomes listed in the definition. | 0-47 days | 

Secondary 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 spirometry value collected at 24 hours post dose within each Treatment Period. | 24hr post dose | 
| Peak FEV1 (Percent Change) | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. | 0 to 4hr | 
| Peak FEV1 (Change From Baseline ) | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. | 0 to 4hr | 
| FEV1 AUC0-24 Area Under the FEV1 Over Time Curve (Change From Baseline) | Spirometry measurements were conducted in accordance with the current ATS/ERS 2005 guidelines. | 0 to 24hr post dose | 
| 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 hours post dose | 
| 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 post dose | 
| AUC0-t Area Under the Plasma Concentration-time Curve From Time Zero to the Last Quantifiable Concentration | Pk parameters are calculated from glycopyrrolate plasma concentration analysed from serial blood samples collected between 0 and 12 hr | 0 to 12 hourr post dose | 
| 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 hours post dose | 
| 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 hours post-dose | 

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