A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging

Inclusion Criteria for Main Study:

• Adult male and female subjects, between 50 and 80 years of age, inclusive, with a body weight > 50 kg and body mass index (BMI) between 19 and 35 kg/m2
• Subjects who have:
• experienced a CV event (acute coronary syndrome, unstable angina, CABG, PCI, stroke, MI, TIA, carotid endarterectomy), but have been clinically stable for at least 6 months since that event,
• or, have peripheral vascular disease (PVD), as indicated by
• symptoms of claudication and either a positive imaging/treadmill test, or
• reduced ankle branchial pressure index,
• or, have a diagnosis of CAD corroborated by stress testing (exercise or pharmacological) or any other confirmed diagnosis of atherosclerotic arterial disease
• Individuals who have experienced a CV event or have PVD will be given preference for enrolment in the study, if they also have one of the following:
• metabolic syndrome, as defined by NCEP ATP III
• Framingham score > 20
• Current smokers (at least 1pack/day)
• Well-controlled diabetes, defined for the purposes of this study as HbA1c 1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin 126mg/dL (7mmol/L) or HbAc1 levels > 8%, at screening. [note: fasting glucose to be checked again at first FDG-PET scan, and if glucose > 11mmol/L at that visit, subject will be excluded from study]
• Positive pre-study hepatitis B surface antigen or positive hepatitis C antibody results within 3 months of screening.
• Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
• Renal impairment with creatinine clearance of 28 units (or an average daily intake of greater than 3 units) for males, or an average weekly intake of > 21 units (or an average daily intake of greater than 2 units) for females. 1 unit is equivalent to a half-pint (284mL) of beer/lager; 25mL measure of spirits or 125mL of wine; or a positive alcohol breath test at the screening visit
• A positive urine test for drugs of abuse (not related to known medications the subject is taking, e.g. codeine for pain management) or alcohol at screening or prior to study medication administration.
• QTc interval > 450 msec (using average value of triplicate ECGs)
• Subjects will be excluded if they have participated in clinical research studies involving radiation in the past three years
• Women must be of non-childbearing potential [i.e. either postmenopausal or documented hysterectomy - tubal ligation is not sufficient]. For the purposes of this study, post menopausal is defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms. Postmenopausal status will be confirmed by serum or urine FSH and oestradiol concentrations at screening, if appropriate. Surgical sterility will be defined as females who have had a hysterectomy and/or bilateral oophorectomy.
• An unwillingness of male subjects to abstain from sexual intercourse with pregnant or lactating women; or an unwillingness of the subject to use a condom/spermicide in addition to having their female partner use another form of contraception such as an IUD, diaphragm with spermicide, injectable progesterone, sub-dermal implants or a tubal ligation if the women could become pregnant from the time of the first dose of the study medication until 3 months after administration of last dose of study medication.

Inclusion Criteria for Subjects in MRI Sub-study

• Recent (in approximately last 12 months) echocardiogram with ejection fraction between 30 and 50%.

Exclusion Criteria for Subjects in MRI Sub-study

• Contraindication to MRI scanning (as assessed by local MRI safety questionnaire) which includes but not limited to:
• Intracranial aneurysm clips (except Sugita) or other metallic objects,
• History of intra- orbital metal fragments that have not been removed by an MD,
• Pacemaker