Clinical trial NCT00555022: Effect of GSK1160724 In Healthy Volunteers
Official title: A Randomized Double-blind, Placebo-controlled, Crossover, Dose Escalation Study to Examine the Safety, Tolerability, Pharmacodynamics and Pharmacokinetics of Single Inhaled Doses of GSK1160724 and Tiotropium Bromide
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Pulmonary Disease, Chronic Obstructive
Keywords: Anticholinergic,
FTIH,
Muscarinic Receptor Antagonist,
Plethysmography
COPD,
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2007-11-07
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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


Eligibility criteria: 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

Primary outcomes:
measure: Number of subjects with adverse events (AEs)
timeFrame: Up to Week 24
measure: Number of subjects with abnormal values for blood pressure
timeFrame: Up to Week 24
measure: Number of subjects with abnormal values for heart rate
timeFrame: Up to Week 24
measure: Number of subjects with abnormal electrocardiogram (ECG) findings
timeFrame: Up to Week 24
measure: Number of subjects with abnormal findings after holter monitoring
timeFrame: Up to 24 hour
measure: Forced expiratory volume in 1 second (FEV1)
timeFrame: Up to Week 24
measure: Forced vital capacity (FVC)
timeFrame: Up to Week 24
measure: Number of subjects having abnormal hematology laboratory parameters
timeFrame: Up to Week 24
measure: Number of subjects with abnormal clinical chemistry parameters
timeFrame: Up to Week 24
measure: Number of subjects with abnormal values for urinalysis
timeFrame: Up to Week 24
measure: Maximum value for resting heart rate over 0-4 hour
timeFrame: Up to 4 hours
measure: Maximum value for resting blood pressure over 0-4 hour
timeFrame: Up to 4 hours
measure: Maximum value for resting ECG over 0-4 hour
timeFrame: Up to 4 hours
measure: Weighted mean of resting heart rate over 0-4 hour
timeFrame: Up to 4 hours
measure: Weighted mean of resting blood pressure over 0-4 hour
timeFrame: Up to 4 hours
measure: Weighted mean of resting ECG over 0-4 hour
timeFrame: Up to 4 hours
Secondary outcomes:
measure: Plasma concentrations of GSK1160724
timeFrame: 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
measure: Plasma concentrations of GSK1762245
timeFrame: 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
measure: Urine concentrations of GSK1160724
timeFrame: 0-2 hours, 2-8 hours, 8-12 hours and 12-24 hours
measure: Urine concentrations of GSK1762245
timeFrame: 0-2 hours, 2-8 hours, 8-12 hours and 12-24 hours
measure: Maximum observed concentration (Cmax) of GSK1160724
timeFrame: 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
measure: Cmax of GSK1762245
timeFrame: 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
measure: Time to Cmax (Tmax) of GSK1160724
timeFrame: 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
measure: Tmax of GSK1762245
timeFrame: 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
measure: Time to last observed plasma concentration (Tlast) of GSK1160724
timeFrame: 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
measure: Tlast of GSK1762245
timeFrame: 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
measure: Area under the plasma concentration time curve from time 0 to last time of quantifiable concentration (AUC [0-T]) of GSK1160724
timeFrame: 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
measure: AUC (0-T) of GSK1762245
timeFrame: 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
measure: Area under the plasma concentration time curve from time 0 to infinity (AUC [0-infinity]) of GSK1160724
timeFrame: 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
measure: AUC (0-infinity) of GSK1762245
timeFrame: 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
measure: The terminal phase elimination rate constant (Lambda z) of GSK1160724
timeFrame: 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
measure: Lambda z of GSK1762245
timeFrame: 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
measure: The Terminal phase half life (T1/2) of GSK1160724
timeFrame: 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
measure: T1/2 of GSK1762245
timeFrame: 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
measure: Serial specific airway conductance (sGaw) response over 24 hours post-dose of GSK1160724 and tiotropium bromide
timeFrame: Up to 24 hours
measure: FEV1 over 24 hours post-dose of GSK1160724 and tiotropium bromide
timeFrame: Up to 24 hours
measure: FVC over 24 hours post-dose of GSK1160724 and tiotropium bromide
timeFrame: Up to 24 hours
measure: Serial sGaw measurements over 48 hours of GSK1160724 and tiotropium bromide
timeFrame: Up to 48 hours
Other outcomes:
Locations:
city: Harrow
country: United Kingdom
facility: GSK Investigational Site
state: Middlesex
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: