A Randomised, Placebo Controlled, Ascending, Repeat Dose Study in Healthy Volunteers Investigating Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of GSK356278

The drug to be given, GSK356278, is a new, investigational compound that may
eventually be used for the treatment of Huntington*s disease. Huntington*s
disease is a progressive, fatal genetic disorder that affects certain parts of
the brain. This disease affects muscle coordination and leads to mental decline
and dementia. The earliest symptoms are a general lack of coordination and an
unsteadiness.
Huntington*s disease is caused by changes in a particular part of the DNA
(contains our genetic information), that normally provides information for a
protein called Huntingtin. This so-called mutation results in a different form
of the Huntingtin protein.
Activation of the mutated Huntingtin protein can eventually lead to damage of
specific areas of the brain that results in Huntington*s disease.

GSK356278 can inhibit the activity of the mutated Huntingtin protein, and
therefore can be useful in the treatment of Huntington*s disease.

To investigate the safety and tolerability of repeat oral doses of GSK356278 in
healthy volunteers.
To investigate the pharmacokinetics of repeat oral doses of GSK356278 in
healthy volunteers.
To evaluate the PK/PD relationship between plasma concentrations and changes in
pharmaco-EEG metrics, cognition and nausea.
To explore food effect on nausea in relation to PK.

Design :
This is a randomised, placebo controlled, ascending repeat dose study in one
cohort of eight healthy volunteers (group 1), one cohort of 12 healthy
volunteers (group 2) and one cohort of 16 healthy volunteers (group 3). Group 1
will receive a repeated dose of GSK356278 or placebo (six active and two
placebo) for 10 days. Group 2 will receive a repeated dose of GSK356278 or
placebo (nine active and three placebo) for 14 days. Group 3 will receive a
single dose of GSK356278 or placebo (twelve active and four placebo), followed
by a repeated dose of GSK356278 or placebo for 28 days.

Group 1
Procedures and assessments
Screening and follow-up: Demographic data, physical examination, medical
history, 24 hr holter, 12-lead electrocardiogram (ECG), vital signs, alcohol
and drug screen, pregnancy test (females only), hepatitis B surface antigen
(HBsAg), anti-hepatitis C virus (HCV), and anti-human immunodeficiency virus
(HIV)1/2, clinical laboratory (including clinical chemistry, haematology,
urinalysis and LFT's), previous and concomitant medication, and Columbia
suicidality assessment;
at eligibility screening: brief physical examination, alcohol and drug screen,
pregnancy test (females only), echocardiography and Columbia suicidality
assessment;
at follow-up: brief physical examination, 12-lead ECG, vital signs and clinical
laboratory (including clinical chemistry, haematology, urinalysis and
troponine, BNP and LFT's)

Observation period: One period in the clinic from Day -2 until Day 14

Blood sampling: For pharmacokinetics of GSK356278 in plasma: pre-dose and 1, 2,
3, 6, 12, 24, and 72 h post-dose Day 1, pre-dose Day 6, pre-dose Day 8,
pre-dose and 1, 2, 3, 6, 12, 24 and 72 h post-dose Day 10.

Safety assessments: Adverse events: throughout the study; 12-lead ECG: pre-dose
predicted Day -1, pre-dose and 1, 2, 4, 6, 12, 24 h post-dose Day 1, pre-dose
and 3 h post-dose Day 5, pre-dose and 1, 2, 4, 6, 12, 24 h post-dose Day 10 and
Day 14; telemetry ECG: Day -1, 1 and 10; vital signs: pre-dose predicted and 1,
2, 3, 4, 6, 12 h post-dose predicted Day -1, pre-dose and 1, 2, 3, 4, 6, and 12
h post-dose Day 1, pre-dose and 3 h post-dose Day 2, 3, 4, 5, 6 and 7,
pre-dose, 1, 2, 3, 4, 6, 12, 24, 48 and 72 h post-dose Day 10 and Day 14;
clinical chemistry, haematology, troponin, BNP and LFT's: Day -1, 2, 4 (LFT's
only), 7 and 11; urinalysis: Day -1, 2 and 11; bond and lader VAS: Day -1, 1, 5
and 10; columbia suicidality assessment: Day 14; echocardiography: Day 12;
inflammation panel and BDNF: Day -1, 2, 7 (inflammatory panel only) and 11

Group 2
Procedures and assessments
Screening and follow-up: Demographic data, physical examination, medical
history, 24 hr holter, 12-lead electrocardiogram (ECG), vital signs, alcohol
and drug screen, pregnancy test (females only), hepatitis B surface antigen
(HBsAg), anti-hepatitis C virus (HCV), and anti-human immunodeficiency virus
(HIV)1/2, clinical laboratory (including clinical chemistry, haematology,
urinalysis and LFT's), previous and concomitant medication, and Columbia
suicidality assessment;
at eligibility screening: brief physical examination, alcohol and drug screen,
pregnancy test (females only), cognitive tests, EEG, echocardiography and
Columbia suicidality assessment;
at follow-up: brief physical examination, 12-lead ECG, vital signs and clinical
laboratory (including clinical chemistry, haematology, urinalysis and troponin,
BNP and LFT's)

Observation period: One period in the clinic from Day -2 until Day 18

Blood sampling: For pharmacokinetics of GSK356278 in plasma: pre-dose and 1, 2,
3, 4, 6, 12, 24, and 72 h post-dose Day 1, pre-dose Day 4, 6, 8, 10, 12,
pre-dose and 1, 2, 3, 4, 6, 12, 24, 48 and 72 h post-dose.

Safety assessments: Adverse events: throughout the study; 12-lead ECG: pre-dose
predicted Day -1, pre-dose and 1, 2, 4, 6, 12, 24 h post-dose Day 1, pre-dose
and 3 h post-dose Day 7, pre-dose and 1, 2, 4, 6 and 12 h post-dose Day 14;
telemetry ECG: Day -1, 1 and 14; vital signs: pre-dose predicted and 1, 2, 3,
4, 6, 12 h post-dose predicted Day -1, pre-dose and 1, 2, 3, 4, 6 and 12 h
post-dose Day 1, pre-dose and 3 h post-dose Day 2, 3, 4, 5, 6, 7, 9 and 11,
pre-dose, 1, 2, 3, 4, 6, 12, 24, 48 and 72 h post-dose Day 14 and Day 18;
clinical chemistry, haematology, troponin, BNP and LFT's: Day -1, 2, 4 (LFT's
only), 7, 10 (LFT's only) and 15; urinalysis: Day -1, 2 and 15; bond and lader
VAS: Day -1, 1, 7 and 14; cognitive tests: Day 2 and 12; EEG: Day 3 and 13;
columbia suicidality assessment: Day 18; echocardiography: Day 16; infalmmation
panel and BDNF: Day -1, 2, 7 (inflammation panel only) and 15

Group 3
Procedures and assessments
Screening and follow-up: Demographic data, physical examination, medical
history, 24 hr holter, 12-lead electrocardiogram (ECG), vital signs, alcohol
and drug screen, pregnancy test (females only), hepatitis B surface antigen
(HBsAg), anti-hepatitis C virus (HCV), and anti-human immunodeficiency virus
(HIV)1/2, clinical laboratory (including clinical chemistry, haematology,
urinalysis and LFT's), previous and concomitant medication, and Columbia
suicidality assessment;
at eligibility screening: brief physical examination, alcohol and drug screen,
pregnancy test (females only), EEG, echocardiography and Columbia suicidality
assessment;
at follow-up: brief physical examination, 12-lead ECG, vital signs and clinical
laboratory (including clinical chemistry, haematology, urinalysis, troponin,
BNP and LFT's)

Observation period:Two periods in the clinic: Period 1: Day -2 until Day 4;
Period 2: Day -1 until Day 32

Blood sampling: For pharmacokinetics of GSK356278 in plasma: pre-dose and 1, 2,
3, 6, 12, 24, 36, 48 and 72 h post-dose Day 1 of period 1, pre-dose and 2 h
post-dose Day 1, pre-dose Day 3 and 5, pre-dose and 3 h post-dose Day 7,
pre-dose Day 9, pre-dose and 2, 4 and 6 h post-dose Day 14, pre-dose Day 21, 24
and 26, pre-dose and 1, 2, 3, 6, 12, 24, 48, 72, 96 h post-dose Day 28 of
period 2.

Urine sampling: For pharmacokinetics: 24 hour collection on Day 28 of period 2.

Safety assessments: Adverse events: throughout the study; 12-lead ECG: pre-dose
predicted Day -1, pre-dose and 1, 2, 4, 6, 12, 24 h post-dose Day 1 of period
1, pre-dose and 3 h post-dose Day 1, 4 and 7, pre-dose and 2 and 4 h post-dose
Day 14, pre-dose and 3 h post-dose Day 21, pre-dose and 1, 2, 3, 6, 12, 24 and
48 h post-dose Day 28 of period 2; telemetry ECG: Day -1 and 1 of period 1 and
Day 28 of period 2; vital signs: pre-dose predicted and 1, 2, 3, 4, 6 and 12 h
post-dose predicted Day -1, pre-dose and 1, 2, 3, 4, 6, 12, 24, 36, 48 and 72 h
post-dose Day 1 of period 1, pre-dose and 2 or 4 h post-dose Day 1, 3, 5, 7, 9
and 11, pre-dose, 2, 4 and 6 h post-dose Day 14, pre-dose and 2 or 4 h
post-dose Day 21, pre-dose and 1, 2, 3, 4, 6, 12, 24, 48, 72 and 96 h post-dose
Day 28 of period 2; clinical chemistry, haematology, troponin, BNP and LFT's:
Day -1 and 2 of period 1, Day 1 (no troponin and BNP), 7, 14, 21 (troponin, BNP
and LFT's only) and 29 of period 2; urinalysis: Day -1 and 2 of period 1, Day
1, 7, 14 and 29 of period 2; bond and lader VAS: Day -1 and 1 of period 1, Day
2 ,7, 14 and 28 of period 2; columbia suicidality assessment: Day -1, 15 and
Day 32 of period 2; EEG: Day -1, 1 and 25 of period 2; cognitive tests: Day -1,
2 and 26 of period 2; echocardiography: Day 13 and 30 of period 2; inflammation
panel: Day -1, 2 of period 1 and Day 4,7,14,21 and 29 of period 2; BDNF: Day 1
and 2 of period 1 and Day 1 and 29 of period 2

Study Medication
Active substance: GSK356278
Activity :PDE4 inhibitor
Indication: Huntington*s disease
Strength: 0.5 * 14 mg
Dosage form: Oral tablet

Treatments
Cohort 1: a repeated dose of 2 mg GSK356278 or placebo on Day 1 until Day 10
Cohort 2: a repeated dose of 5 mg GSK356278 or placebo on Day 1 until Day 14
Cohort 3: a single dose of 10 mg GSK356278 or placebo on Day 1 of period 1, and
a repeated dose of 10 mg GSK356278 or placebo on Day 1 until Day 28 of period 2

Procedures: pain, light bleeding, heamatoma, possibility of an infetcion

See E9