Clinical trial NCT01703624: Dose Ranging Study of Glycopyrronium Bromide in Patients With Moderate or Severe Chronic Obstructive Pulmonary Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Chronic Obstructive Pulmonary Disease
Keywords: glycopyrronium bromide
glycopyrrolate
oral inhalation
COPD
chronic obstructive pulmonary disease
lung function
pharmacokinetics
tolerability
safety
cross-over
single-dose
dose-ranging
Lead sponsor: Prosonix Limited
Sponsor class: INDUSTRY
First posted: 2012-10-10
Enrollment: 37
Sex: ALL
Minimum age (years): 40
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Forced Expiratory Volume in one second (FEV1) Area Under the Curve (AUC)
timeFrame: From time zero to 24-hours
Secondary outcomes:
measure: Forced Expiratory Volume in one second (FEV1) Area Under the Curve (AUC)
timeFrame: From time zero to 12-hours
measure: Forced Expiratory Volume in one second (FEV1) Area Under the Curve (AUC)
timeFrame: From 12 to 24-hours
measure: Forced Expiratory Volume in one second (FEV1)
timeFrame: From time zero to 24-hours
measure: Forced Vital Capacity (FVC) Area Under the Curve (AUC)
timeFrame: From time zero to 24-hours
measure: Forced Expiratory Volume in one second (FEV1) / Forced Vital Capacity (FVC) ratio
timeFrame: From time zero to 24-hours
measure: Number of subjects reporting adverse events after each treatment as a measure of safety and tolerability
timeFrame: An average of 9 weeks
measure: Systolic blood pressure
timeFrame: From time zero to 24-hours
measure: Diastolic blood pressure
timeFrame: From time zero to 24-hours
measure: Peripheral pulse rate
timeFrame: From time zero to 24-hours
measure: Electrocardiography (ECG)
timeFrame: From time zero to 24-hours
measure: Clinical hematology
timeFrame: An average of 9 weeks
measure: Clinical chemistry
timeFrame: An average of 9 weeks
measure: Plasma glycopyrronium bromide concentration-time Area Under the Curve (AUC)
timeFrame: From time zero to 24-hours
measure: Plasma glycopyrronium bromide peak concentration (Cmax)
timeFrame: From time zero to 24-hours
measure: Plasma glycopyrronium bromide time to maximum concentration (tmax)
timeFrame: From time zero to 24-hours
measure: Plasma glycopyrronium bromide concentration elimination half-life (t1/2)
timeFrame: From time zero to 24-hours
measure: Glycopyrronium bromide total plasma clearance following extravascular administration (CL/F)
timeFrame: From time zero to 24-hours
measure: Glycopyrronium bromide apparent volume of distribution following extravascular administration (Vz/F)
timeFrame: From time zero to 24-hours
Other outcomes:
Locations:
city: Manchester
country: United Kingdom
facility: Medicines Evaluation Unit
Study officials:
affiliation: Prosonix Limited, Oxford, UK
name: Geoff Down, MB BS FFPM
role: STUDY_DIRECTOR
affiliation: Medicines Evaluation Unit, Manchester, UK
name: Dave Singh, MA MD MRCP
role: PRINCIPAL_INVESTIGATOR
References: