Effect of GSK1160724 In Healthy Volunteers

GlaxoSmithKline21 enrolled

Overview

GSK1160724 is a potent mAChR antagonist, which is being developed for treatment of chronic obstructive pulmonary disease (COPD)

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Enrollment

Conditions

Pulmonary Disease, Chronic Obstructive

Interventions

GSK1160724DRUG

GSK1160724 will be available with dosing strengths of 10, 50 and 125 micrograms/blister for inhalation using the DISKUS inhaler.

Tiotropium bromideDRUG

Tiotropium bromide capsules will be supplied with a dose of 18 micrograms administered via a HandiHaler device.

PlaceboDRUG

Subjects will receive placebo.

Eligibility

Sex: ALLMin age: 18 YearsMax age: 55 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: * Healthy male and female subjects. Female subjects must be of non-child bearing potential. * Aged between 18-55 years inclusive * Non-smokers * Normal spirometry * A signed and dated written informed consent is obtained from the subject * The subject is capable of giving informed consent, which includes compliance with the requirements and restrictions listed in the consent form * Available to complete the study * The subject is greater than or equal to 50kg with a body mass index within the range 19.0 to 29.9 kg/m2 inclusive * Response to ipratropium bromide Exclusion Criteria: * Any clinically relevant and important abnormality identified at the screening medical assessment (physical examination/medical history), clinical laboratory tests, or ECG (12-lead or Holter) * A history of breathing problems * A mean QTc(B) value \> 450ms, the QTc(B) of the 3 screening ECGs are not within 10% of the mean, a PR interval outside the range 90-210ms or an ECG that is not suitable for QT measurements at screening * A history of elevated resting blood pressure or a mean blood pressure higher than 140/90 mmHg at screening * A mean heart rate outside the range 40-90 bpm inclusive at screening * History of use of tobacco- or nicotine-containing products within 6 months of screening, and/or positive urine cotinine test results at screening * Where participation in the study would result in donation of blood in excess of 500mL within a 56 day period at screening * The subject is currently taking regular (or a course of) medication, whether prescribed or not, including herbal remedies such as St John's Wort etc. The subject has taken: * prescription medications for 14 days prior to first dose of study drug, or * Over-the-counter (OTC) medications/preparations (including herbal remedies, etc.) excluding simple analgesics for 48 hours prior to first dose of study drug,unless it is judged by the Investigator not to compromise the subject's safety or influence the outcome of the study. * The subject has participated in a study with a new molecular entity or any other trial within a period of 3 months prior first dose of study drug * The subject has tested positive for hepatitis C antibody (third generation enzyme immunoassay), hepatitis B surface antigen or HIV antibodies (if tested according to site SOP's) at screening. * The subject has tested positive for drugs-of-abuse at screening * The subject has tested positive for urine alcohol (including ethanol) at screening The detection of alcohol would not be an exclusion at screening but would need to be negative pre-dose and during the study * The subject is unable to use the DISKUS™ and/or HandiHaler inhaler devices correctly at screening * The subject has a suspected history of alcohol abuse within the six months previous to the screening visit * The subject has a known allergy or hypersensitivity to magnesium stearate, milk protein or the excipient lactose monohydrate, iodine, ipratropium bromide, tiotropium bromide, atropine and/or any of its derivatives * The subject has a significant clinical history of prostatic hypertrophy or narrow angle glaucoma * The subject has received an allogeneic bone marrow transplant * The subject has claustrophobia that may be aggravated by entering the whole body plethysmography cabinet

Locations (1)

GSK Investigational Site

Harrow, Middlesex, United Kingdom

Outcomes

Primary Outcomes

Number of subjects with adverse events (AEs)

An AE is any untoward medical occurrence in a clinical study subjects, temporally associated with the use of a study treatment, whether or not considered related to the study treatment.

Time frame: Up to Week 24

Number of subjects with abnormal values for blood pressure

Systolic and diastolic blood pressure will be measured in a semi-recumbent position after 5 minutes rest.

Time frame: Up to Week 24

Number of subjects with abnormal values for heart rate

Heart rate will be measured in a semi-recumbent position after 5 minutes rest.

Time frame: Up to Week 24

Number of subjects with abnormal electrocardiogram (ECG) findings

Triplicate 12-lead ECGs will be measured in a semi-recumbent position after 5 minutes rest at each time point using ECG machine.

Time frame: Up to Week 24

Number of subjects with abnormal findings after holter monitoring

Holter monitoring will be conducted at 24 hour.

Time frame: Up to 24 hour

Forced expiratory volume in 1 second (FEV1)

Lung function will be measured by FEV1, defined as the maximal amount of air that can be forcefully exhaled in one second.

Time frame: Up to Week 24

Forced vital capacity (FVC)

Lung function will be measured by FVC, defined as the amount of air which can be forcibly exhaled from the lungs after taking the deepest breath possible.

Time frame: Up to Week 24

Data from ClinicalTrials.gov

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Secondary Outcomes

Plasma concentrations of GSK1160724

Plasma samples will be collected at the indicated time points to measure the concentration of GSK1160724.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Plasma concentrations of GSK1762245

Plasma samples will be collected at the indicated time points to measure the concentration of the active metabolite GSK1762245.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Urine concentrations of GSK1160724

Urine samples will be collected at the indicated time points to measure the concentration of GSK1160724.

Time frame: 0-2 hours, 2-8 hours, 8-12 hours and 12-24 hours

Urine concentrations of GSK1762245

Urine samples will be collected at the indicated time points to measure the concentration of the active metabolite GSK1762245.

Time frame: 0-2 hours, 2-8 hours, 8-12 hours and 12-24 hours

Maximum observed concentration (Cmax) of GSK1160724

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Cmax of GSK1762245

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Time to Cmax (Tmax) of GSK1160724

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Tmax of GSK1762245

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Time to last observed plasma concentration (Tlast) of GSK1160724

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Tlast of GSK1762245

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Area under the plasma concentration time curve from time 0 to last time of quantifiable concentration (AUC [0-T]) of GSK1160724

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

AUC (0-T) of GSK1762245

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Area under the plasma concentration time curve from time 0 to infinity (AUC [0-infinity]) of GSK1160724

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

AUC (0-infinity) of GSK1762245

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

The terminal phase elimination rate constant (Lambda z) of GSK1160724

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Lambda z of GSK1762245

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

The Terminal phase half life (T1/2) of GSK1160724

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

T1/2 of GSK1762245

Blood samples will be collected at the indicated time points for pharmacokinetic analysis.

Time frame: Pre-dose, 5 minutes, 15 minutes, 30 minutes, 1 hour, 1.5 hours, 2 hours, 4 hours, 6 hours, 8 hours.12 hours, 16 hours, 24 hours, 48 hours Post-dose

Serial specific airway conductance (sGaw) response over 24 hours post-dose of GSK1160724 and tiotropium bromide

The sGaw response will be assessed by whole body plethysmograph at the indicated timepoints.

Time frame: Up to 24 hours

FEV1 over 24 hours post-dose of GSK1160724 and tiotropium bromide

The sGaw response will be assessed by whole body plethysmograph at the indicated timepoints.

Time frame: Up to 24 hours

FVC over 24 hours post-dose of GSK1160724 and tiotropium bromide

The sGaw response will be assessed by whole body plethysmograph at the indicated timepoints.

Time frame: Up to 24 hours

Serial sGaw measurements over 48 hours of GSK1160724 and tiotropium bromide

The sGaw is a measure of the change in specific airway conductance. It will be assessed by whole body plethysmograph at the indicated timepoints.

Time frame: Up to 48 hours