This protocol is designed to explore whether short-term therapy with GSK1278863 affects PASP under normoxic and hypoxic conditions in healthy volunteers. Healthy subjects will be evaluated using echocardiography to estimate PASP based on the velocity of the tricuspid regurgitant jet. Resting PASP will be assessed under normoxic (room air) conditions, as well as after 30 minutes' exposure to 15% O2 before, during, and after short-term treatment with GSK1278863.
This is a single-center, randomized, placebo-controlled, single-blinded (subjects and investigators will be blinded, GSK internal personnel will not be blinded) study designed to test whether short-term administration (5 days) of GSK1278863 affects PASP under normoxic and hypoxic conditions in healthy volunteers. Approximately 45 healthy subjects with mild-moderate baseline tricuspid regurgitation (sufficient to allow reliable assessment of PASP) will be enrolled into this study and will provide \~15 evaluable subjects in each arm \[Placebo, 5 mg, and 100 mg GSK 1278863\].
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
SINGLE
Enrollment
49
GSK1278863
Placebo
GSK Investigational Site
Baltimore, Maryland, United States
Placebo-adjusted change from baseline in PASP (estimated by transthoracic echocardiography) under normoxic conditions following 5 days of GSK1278863
Time frame: Day 5
Placebo-adjusted change from baseline in PASP under normoxic and hypoxic conditions 8 hours after the first dose of study treatment
8 hours
Time frame: Day 1
Placebo-adjusted change from baseline in PASP under normoxic and hypoxic conditions following 1 day of therapy
Time frame: Day 1
Placebo-adjusted change from baseline in PASP under normoxic and hypoxic conditions 8 hours after the fifth dose of study treatment
8 hours
Time frame: Day 5
Placebo-adjusted change from baseline in PASP under hypoxic conditions following 5 days of GSK1278863
Time frame: Day 5
Clinical safety and tolerability data including AE reporting, ECGs, vital signs, physical exam findings and clinical laboratory values, including hematologic parameters
Through-out the study
Time frame: Day 5
Plasma pharmacokinetics (AUC, Cmax, Tmax, T1/2, etc.) of GSK1278863 and its circulating metabolites (M2, M3, M4, M5, M6 and M13)
Through-out the study
Time frame: Day 5
RV size, RV ejection fraction, severity of tricuspid regurgitation, right ventricular outflow tract acceleration time at all time points at which echocardiograms are obtained (as data permit)
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Exploratory outcomes; through-out the study
Time frame: Day 5
Biomarker/PD endpoints may include EPO, endothelin-1 and hepcidin or other markers of PHD or HIF activity, as data permit
Exploratory outcomes; through-out the study
Time frame: Day 5