Dose Ranging Study of Glycopyrronium Bromide in Patients With Moderate or Severe Chronic Obstructive Pulmonary Disease

Study Overview
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Brief Summary
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This is an investigation of the beneficial effects, tolerability and safety of a range of single doses of orally inhaled glycopyrronium bromide (PSX1002GB pMDI) in male and female patients with moderate or severe chronic obstructive pulmonary disease (COPD). COPD is a long term and progressive disease of the lungs, generally caused by cigarette smoking, but other factors may be involved. Glycopyrronium bromide (GB) appears to be particularly useful in dilating the constricted airways of such patients, with a duration of action variously described as being between 12 and 24 hours. This study will investigate how well tolerated and safe this medication is at a range of doses. It will also help in the selection of a suitable dose for larger and repeat dose studies, based on measures of lung response. It will also help to determine how often the medication should be given; twice daily, or once daily. Up to 40 patients will be enrolled into the study, ranging in age from 40 to 75 years of age. Patients will be medically assessed before participation to ensure their suitability. The study will take place in one centre in the UK over five sessions; at each session one dose (2 puffs) of GB or one dose (2 puffs) of placebo will be administered from a simple inhaler device. Neither staff nor patients will know which dose, or if placebo, is being taken. Lung function will be measured for up to 26 hours after the administration of each dose using standard spirometry equipment. Blood samples will be taken over a 24-hour period to check the blood levels of GB. There will be a period of about a week between each dosing session. Patients will be medically reviewed after the study to confirm that no untoward effects are present.

Official Title
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An Investigation of the Efficacy, Tolerability and Safety of a Range of Doses of Orally Inhaled Glycopyrronium Bromide (PSX1002-GB pMDI) in Male and Female Patients With Moderate or Severe Chronic Obstructive Pulmonary Disease

Conditions
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Chronic Obstructive Pulmonary Disease

Intervention / Treatment
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* Drug: glycopyrronium bromide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female age 40-75 years, inclusive A clinical diagnosis of moderate to severe COPD (GOLD guidelines) Current smokers or ex-smokers with at least 10-pack year smoking history Post-bronchodilator FEV1/FVC ratio < 70 % at Screen Post-bronchodilator FEV1 ≥ 40 % to < 80 % of predicted at Screen Demonstrated to be responsive to ipratropium (defined as at least an 100ml increase in FEV1 following ipratropium 80 µg) Ability to perform acceptable spirometry (ATS/ERS guidelines) 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 an acceptable means of birth control throughout the study (defined in protocol) 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 (defined in protocol) Recent history of hospitalisation due to an exacerbation of airway disease within three months prior to the Screening Visit or randomisation Need for increased treatments of COPD within six weeks prior to the Screening Visit or randomisation Primary diagnosis of asthma Prior lung volume reductions surgery or history of chest/lung irradiation Regular use of daily oxygen therapy Use of systemic steroids within three months prior to the Screening Visit or during the run-in period Respiratory tract infection within six weeks prior to the Screening Visit. History of tuberculosis, bronchiectasis or other non-specific pulmonary disease History of urinary retention or bladder neck obstructive type symptoms History of narrow-angle glaucoma Clinically significant abnormal ECG Positive Hepatitis B antigen or positive Hepatitis C antibody Positive screening test for HIV antibodies Current evidence or history of excessive use or abuse of alcohol in the opinion of the Investigator Current evidence or history of abusing legal drugs or use of illegal drugs or substances in the opinion of the Investigator Donation of 450 ml or more of blood within eight weeks of the Screening Visit 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. Inability to comply with study procedures or with study treatment intake, including inability to be trained and/or inability to demonstrate good inhaler technique with Vitalograph AIM

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: glycopyrronium bromide 12.5mcg<br>glycopyrronium bromide 12.5mcg single dose via pressurised metered dose inhaler (pMDI) | Drug: glycopyrronium bromide<br>* glycopyrronium bromide suspension in HFA<br>* Other names: PSX1002-GB;|
| Experimental: glycopyrronium bromide 25mcg<br>glycopyrronium bromide 25mcg single dose via pressurised metered dose inhaler (pMDI) | Drug: glycopyrronium bromide<br>* glycopyrronium bromide suspension in HFA<br>* Other names: PSX1002-GB;|
| Experimental: glycopyrronium bromide 50mcg<br>glycopyrronium bromide 50mcg single dose via pressurised metered dose inhaler (pMDI) | Drug: glycopyrronium bromide<br>* glycopyrronium bromide suspension in HFA<br>* Other names: PSX1002-GB;|
| Experimental: glycopyrronium bromide 100mcg<br>glycopyrronium bromide 100mcg single dose via pressurised metered dose inhaler (pMDI) | Drug: glycopyrronium bromide<br>* glycopyrronium bromide suspension in HFA<br>* Other names: PSX1002-GB;|
| Placebo Comparator: placebo<br>placebo single dose via pressurised metered dose inhaler (pMDI) | Drug: glycopyrronium bromide<br>* glycopyrronium bromide suspension in HFA<br>* Other names: PSX1002-GB;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in one second (FEV1) Area Under the Curve (AUC) | FEV1 time-adjusted AUC(0-24 hours) | From time zero to 24-hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume in one second (FEV1) Area Under the Curve (AUC) | FEV1 time-adjusted AUC(0-12 hours) | From time zero to 12-hours | 
| Forced Expiratory Volume in one second (FEV1) Area Under the Curve (AUC) | FEV1 time-adjusted AUC(12-24 hours) | From 12 to 24-hours | 
| Forced Expiratory Volume in one second (FEV1) | Serial FEV1 time-point assessments | From time zero to 24-hours | 
| Forced Vital Capacity (FVC) Area Under the Curve (AUC) | FVC time-adjusted AUC(0-24 hours), AUC(0-12 hours), AUC(12-24 hours), serial time-point assessment | From time zero to 24-hours | 
| Forced Expiratory Volume in one second (FEV1) / Forced Vital Capacity (FVC) ratio | Serial FEV1/FVC time-point assessment | From time zero to 24-hours | 
| Number of subjects reporting adverse events after each treatment as a measure of safety and tolerability | Adverse event monitoring will begin once a subject provides informed consent and will continue until study participation is concluded; incidence rates will be summarised by system organ class, preferred term, severity and by reported relationship to study drug for each treatment | An average of 9 weeks | 
| Systolic blood pressure | Descriptive statistics will be presented for the serial measurements by treatment | From time zero to 24-hours | 
| Diastolic blood pressure | Descriptive statistics will be presented for the serial measurements by treatment | From time zero to 24-hours | 
| Peripheral pulse rate | Descriptive statistics will be presented for the serial measurements by treatment | From time zero to 24-hours | 
| Electrocardiography (ECG) | Descriptive statistics will be presented for the serial measurements of each of the standard electrocardiographic (12-lead) parameters by treatment | From time zero to 24-hours | 
| Clinical hematology | Clinical hematology measures will be taken at the Screening Visit and at the Safety Follow-up Visit and will consist of: red blood cell count, hemoglobin, hematocrit, mean cell hemoglobin, mean cell hemoglobin concentration, mean cell volume, white blood cell count, differential white blood cell count and platelet count. Data will be summarised using descriptive statistics | An average of 9 weeks | 
| Clinical chemistry | Clinical chemistry measures will be taken at the Screening Visit and at the Safety Follow-up Visit and will consist of: sodium, potassium, urea, creatinine, uric acid, glucose, calcium, inorganic phosphorus, total bilirubin, alkaline phosphatase, alanine transaminase, aspartate transminase, gamma glutamyl transferase, creatine kinase, total protein, albumin, cholesterol and triglycerides. Data will be summarised using descriptive statistics | An average of 9 weeks | 
| Plasma glycopyrronium bromide concentration-time Area Under the Curve (AUC) | AUC (0-infinity) will be extrapolated from serial measures taken over time zero to 24-hours. The descriptive statistics presented by treatment will be: minimum, median, maximum, geometric mean, arithmetic mean and arithmetic standard deviation | From time zero to 24-hours | 
| Plasma glycopyrronium bromide peak concentration (Cmax) | Cmax will be obtained from serial measures taken over time zero to 24-hours. The descriptive statistics presented by treatment will be: minimum, median, maximum, geometric mean, arithmetic mean and arithmetic standard deviation | From time zero to 24-hours | 
| Plasma glycopyrronium bromide time to maximum concentration (tmax) | tmax will be calculated from serial measures taken over time zero to 24-hours. The descriptive statistics presented by treatment will be: minimum, median, maximum, geometric mean, arithmetic mean and arithmetic standard deviation | From time zero to 24-hours | 
| Plasma glycopyrronium bromide concentration elimination half-life (t1/2) | t1/2 will be calculated from serial measures taken over time zero to 24-hours. The descriptive statistics presented by treatment will be: minimum, median, maximum, geometric mean, arithmetic mean and arithmetic standard deviation | From time zero to 24-hours | 
| Glycopyrronium bromide total plasma clearance following extravascular administration (CL/F) | CL/F will be calculated from serial plasma concentration measures taken over time zero to 24-hours. The descriptive statistics presented by treatment will be: minimum, median, maximum, geometric mean, arithmetic mean and arithmetic standard deviation | From time zero to 24-hours | 
| Glycopyrronium bromide apparent volume of distribution following extravascular administration (Vz/F) | Vz/F will be calculated from serial plasma concentration measures taken over time zero to 24-hours. The descriptive statistics presented by treatment will be: minimum, median, maximum, geometric mean, arithmetic mean and arithmetic standard deviation | From time zero to 24-hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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glycopyrronium bromide, glycopyrrolate, oral inhalation, COPD, chronic obstructive pulmonary disease, lung function, pharmacokinetics, tolerability, safety, cross-over, single-dose, dose-ranging