The study drug, GSK356278, is a possible new medicine for the treatment of Huntington's disease. Huntington's disease, which is often called HD, is caused by a faulty gene that is passed down through families. HD causes damage to nerve cells in the brain which causes them to waste away. As the damage progresses patients develop symptoms that affect every aspect of life. HD reduces people's ability to walk, talk, think, communicate and causes uncontrolled movements. GSK356278 may slow down the progression of damage to nerve cells in people with HD and help with their ability to think. GSK356278 was well tolerated when it was given as a single dose to healthy people. In this study we want to see what effects, both good and bad, GSK356278 has in people when it is taken every day. During the study we will look at about 3 different doses of GSK356278 in about 36 healthy people. The study will also look at how GSK356278 tablets behave in the body after it is swallowed (this is called pharmacokinetics). The study will also look at effects of GSK356278 on the body (this is called pharmacodynamics). The study will help to design future clinical studies with GSK356278.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
BASIC_SCIENCE
Masking
SINGLE
Enrollment
36
Cohort 1: A dose of 2mg per day for 10 days; Cohort 2: A dose of Xmg for 14 days. the dose will be determined from Cohort 1 not to exceed 14 mg; Cohort 3: a single dose of Ymg with a wash out of 7 days followed by 28 days of repeat dosing. The dose (Ymg) will be determined from cohort 1 and 2 not to exceed 14 mg.
Cohort 1, a placebo per day for 10 days Cohort 2, a placebo per day for 14 days Cohort 3, a single placebo with a wash out of 7 days followed by 28 days of repeat dosing of a placebo per day.
GSK Investigational Site
Zuidlaren, Netherlands
Composite (or Profile) of Pharmacokinetics
The primary pharmacokinetic endpoints following oral administration are: peak plasma concentration (Cmax), time of peak plasma concentration (tmax), area under the plasma concentration-time curve over the dose interval , and area under the plasma concentration-time curve from time-zero extrapolated to infinite time, accumulation ratio (Ro), terminal half-life (t½ ), apparent oral clearance (CL/F) and trough concentration.
Time frame: Cohort 1 for 288 hours post dose; Cohort 2 for 384 hours post dose; Cohort 3 single dose session for 72 hours; Cohort 3 repeat dose session for 744 hours post dose.
Safety and tolerability parameters including change from baseline measures for vital signs
Time frame: Cohort 1 for 15 days post dose; Cohort 2 for 19 days post dose; Cohort 3 single dose session for 4 days post dose; Cohort 3 repeat dose for 33 days post dose.
Safety and tolerability parameters including change from baseline for 12-lead ECGs
Time frame: Cohort 1 for 15 days post dose; Cohort 2 for 19 days post dose; Cohort 3 single dose session for 4 days post dose; Cohort 3 repeat dose for 33 days post dose.
Safety and tolerability parameters including change from baseline for telemetry ECGs
Time frame: Cohort 1 for 8 hours 30 minutes on Day 1 and Day 10; Cohort 2 for 8 hours 30 minutes on Day 1 and Day 14; Cohort 3 single dose session for 8 hours 30 minutes on Day 1; Cohort 3 repeat dose for 8 hours 30 minutes on Day 1 on Day28.
Safety and tolerability parameters including change from baseline for clinical laboratory tests
hematology, chemistry, liver function enzymes, troponin, B-type natriuretic peptide, inflammatory markers (Haptoglobin, fibrinogen, CRP, IL-6) and urinalysis
Time frame: Cohort 1 for up to 28 days; Cohort 2 for up to 32 days; Cohort 3 single dose for 2 days; Cohort 3 repeat dose for up to 46 days
Safety and tolerability parameters including change from baseline for clinical lab tests
Inflammatory markers (Haptoglobin, fibrinogen, CRP, IL-6)
Time frame: Cohort 1 for 11 days; Cohort 2 for 15 days; Cohort 3 single dose for 2 days; Cohort 3 repeat dose for 29 days
Safety and tolerability parameters including change from baseline for echocardiography
Time frame: Cohort 1 for 12 days; Cohort 2 for 16 days; Cohort 3 repeat dose for 30 days
Safety and tolerability parameters including change from baseline for Bond and Lader VAS
Time frame: Cohort 1 for 10 days; Cohort 2 for 14 days; Cohort 3 single dose for 2-3 hours post dose on Day 1; Cohort 3 repeat dose for 28 days
Safety and tolerability parameters including change from baseline for Columbia Suicide Severity Rating Scale (C-SSRS)
Time frame: Cohort 1 for 14 days; Cohort 2 for 18 days; Cohort 3 repeat dose for 32 days
Safety and tolerability parameters including change from baseline for Rhodes Index of Nausea, Vomiting and Retching
Time frame: Cohort 1 for 11 days; Cohort 2 for 15 days; Cohort 3 single dose for 2 days; Cohort 3 repeat dose for 28 days
Safety and tolerability parameters including change from baseline in the collection of adverse events
Time frame: Cohort 1 for 14 days; Cohort 2 for up to 32 days; Cohort 3 single dose for 4 days; Cohort 3 repeat dose for up to 46 days
Pharmacodynamic parameters including change from baseline for electroencephalography
Time frame: Cohort 2 for 13 days Cohort 3 repeat dose for 25 days
Pharmacodynamic parameters including change from baseline for cognition test
Time frame: Cohort 2 for 12 days Cohort 3 repeat dose for 26 days
Pharmacodynamic parameters including change from baseline for plasma Brain-derived neurotrophic factor
Time frame: Cohort 1 for 11 days; Cohort 2 for 15 days; Cohort 3 single dose session for 2 days; Cohort 3 repeat dose session for 29 days
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