This study is the first administration of GSK2982772 in humans. The study will evaluate the safety, tolerability, pharmacokinetics (PK), and exploratory pharmacodynamics (PD) of single and repeat oral doses of up to 14 days with GSK2982772 in healthy male subjects. This study is planned to include approximately 52 subjects and will consist of 2 parts: Part A - single ascending dose, randomized, placebo controlled, 4 way crossover. In addition to the crossover treatment periods, up to 8 subjects in cohort 2 will participate in an additional treatment period and receive GSK2982772 with a high-fat meal. Part B - repeat dose, randomized, placebo controlled, sequential-group. In both cohorts of Part A (Cohorts 1 and 2), subjects will be randomized equally (1:1:1:1) to one of 4 treatment sequences. Within each period, allocation of active to placebo treatment will be 3:1. In all cohorts in Part B (Cohorts 3, 4 and 5) subjects will be randomized to GSK2982772 or placebo in a 3:1 ratio. If required, subjects in the additional cohorts in Part A (Cohort 6) and Part B (Cohort 7) will be randomized to GSK2982772 or placebo in a 1:1:1:1 and 3:1 ratio, respectively. The study duration, including screening and follow-up, is not expected to exceed 105 days for any subject in the study.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
DOUBLE
Enrollment
79
Clear, colorless solution containing GSK2982772 in water with 5% ethanol (0.1mg/mL). Administered orally in required volumes for dosing less than 5mg
Size 00 White Opaque capsule containing GSK2982772 as white to almost white solid. Administered orally with water for dosing from 5 to 120 mg
Clear, colorless solution containing placebo in water with 5% ethanol (0.1mg/mL). Administered orally in required volumes for dosing less than 5mg
Size 00 White Opaque capsule containing Placebo as white to almost white solid
GSK Investigational Site
Cambridge, United Kingdom
Safety and tolerability of GSK2982772 as assessed by clinical monitoring and reporting of adverse events (AE) and serious adverse events (SAE)
AEs and SAEs will be collected from the start of Study Treatment until the follow-up contact
Time frame: Up to approximately 105 days
Change in laboratory values after single (fed and fasted) and repeat doses of GSK2982772
Laboratory assessments will include analysis of hematology parameters, clinical chemistry, routine urinalysis, lipid panel (Part B Only) and other screening Tests
Time frame: Up to approximately 105 days
Electrocardiogram (ECG) assessment after single (fed and fasted) and repeat doses of GSK2982772
12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and QT duration corrected for heart rate by Fridericia's formula (QTcF) intervals. Triplicate 12-lead ECGs will be obtained pre-dose on Day 1 and Day 14 (Part B only).
Time frame: Up to approximately 105 days
Change in vital signs after single (fed and fasted) and repeat doses of GSK2982772
Vital signs will be measured in semi-supine position after short period of time (e.g., 5 to 10 minutes rest) and will include systolic and diastolic blood pressure, temperature, pulse rate, pulse oximetry (SpO2), and respiratory rate. Triplicate vital signs will be obtained pre-dose on Day 1 and Day 14 (Part B only)
Time frame: Up to approximately 105 days
Summary of physical examinations after single (fed and fasted) and repeat doses of GSK2982772
A complete physical examination will include assessment of the Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Weight will also be measured and recorded. A brief physical examination will include assessments of the skin, lungs, cardiovascular system, abdomen (liver and spleen), and assessment for lymphadenopathy
Time frame: Up to approximately 105 days
Composite of derived Pharmacokinetic (PK) parameters of GSK2982772 measured by AUC (0-t), AUC (0-infinity), Cmax, Tmax and t1/2,following single (fed and fasted) doses
PK parameters for GSK2982772 will include area under the blood drug concentration versus time curve from time zero (pre-dose) to last time of quantifiable concentration within a subject across all treatments (AUC \[0-t\]), area under the concentration-time curve from time zero (pre-dose) extrapolated to infinite time (AUC \[0-infinity\]), maximum observed blood drug concentration (Cmax), time to maximum observed blood drug concentration (Tmax), and terminal half-life (t1/2) following single (fed and fasted) doses, where data allow
Time frame: Pre-dose, Days 1 (20 and 40 minutes, 1, 1.5, 2, 3, 5, 8, 10 and 12 hours), 2 and 3 post dose
Composite of derived blood PK parameters of GSK2982772 measured by AUC (0-t), AUC (0-infinity), AUC (0-tau), Cmax, Tmax and t1/2,following repeat doses
Derived blood PK parameters for GSK2982772 will include AUC(0-t), AUC(0-infinity), area under the concentration-time curve over the dosing interval (AUC \[0-tau\]), Cmax, Tmax and t1/2, following single and repeat doses
Time frame: Pre-dose, Days 1 (20 and 40 minutes, 1, 1.5, 2, 3, 5, 8, 10 and 12 hours) , 2, 3, 4, 5, 6, 7, 14 (20 and 40 minutes, 1, 1.5, 2, 3, 5, 8, 10 and 12 hours), 15 and 16 post-dose
Estimation of accumulation ratio (Ro) of GSK2982772 following single and repeat doses
Ro will be calculated as the ratio of AUC(0-24) (Repeat Dose) to AUC(0-24) (Single Dose). Day 14 (Repeat Dose) will be compared with Day 1 (Single Dose) in order to estimate the accumulation ratio for each dose level
Time frame: Up to Day 14 of Part B
Ratio of Plasma 4beta-hydroxycholesterol to cholesterol during pre-treatment and following repeat dosing of GSK2982772
A comparison will be made between the ratio of 4beta-hydroxycholesterol: cholesterol at baseline and on Day 14 to assess potential changes in cytochrome P450 isoform 3A4(CYP3A4) enzyme activity following GSK2982772 treatment.
Time frame: Up to Day 14 of Part B
Ex-vivo GSK2982772 blood:plasma concentration ratio over a range of concentrations and % blood cell association.
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.
Time frame: Up to approximately 105 days