A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging
A Study to Evaluate the Effects of 3 Months Dosing With GW856553, as Assessed FDG-PET/CT Imaging
This study is being conducted to assess the potential anti-inflammatory effects of a 3-month
 treatment with GW856553, on the inflammatory activity within the aorta and carotid plaques,
 as assessed by FDG-PET/CT.
Inclusion Criteria for Main Study:

 1. 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

 2. 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 <=
 8%, or fasting blood glucose <= 126mg/dL (7mmol/L)

 3. Subjects must be on a stable dose of statin for at least 3 months prior to first dose
 of study medication. Subjects must be capable of continuing statin therapy from
 screening until the final follow up visit.

 4. Either carotid or aortic TBR ³ 1.6, as measured on FDG-PET/CT, signifying active
 inflammation.

 5. AST and ALT < 2xULN at screening; alkaline phosphatase and bilirubin <= 1.5xULN at
 screening (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and
 direct bilirubin <35%).

 6. A signed and dated written informed consent prior to admission to the study

 7. The subject is able to understand and comply with protocol requirements, instructions
 and protocol-stated restrictions.

 Exclusion Criteria for Main Study:

 1. Any medical history or clinically relevant abnormality identified on the screening
 medical examination, vital sign measurement, 12-lead ECG recording and/or clinical
 laboratory examination that is deemed by the principal investigator and/or medical
 monitor to make the subject ineligible for inclusion because of a safety concern.

 2. History of heart failure defined as NYHA class II - IV or those with known severe LV
 systolic dysfunction (EF<30%) regardless of symptomatic status

 3. Subjects with atrial fibrillation (AF) at screening will be excluded.

 4. Insulin controlled Type 1 or Type 2 diabetics

 5. Diabetics with fasting glucose > 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]

 6. Positive pre-study hepatitis B surface antigen or positive hepatitis C antibody
 results within 3 months of screening.

 7. Current or chronic history of liver disease, or known hepatic or biliary abnormalities
 (with the exception of Gilbert's syndrome or asymptomatic gallstones).

 8. Renal impairment with creatinine clearance of <40 ml/min at screening, or history of
 kidney transplant or history of contrast nephropathy.

 9. Subjects with rheumatoid arthritis, connective tissue disorders and other conditions
 known to be associated with active chronic inflammation (e.g. Inflammatory Bowel
 Disease).

 10. Subjects with chronic infections such as HIV, gingivitis, periodonitis, prostatitis,
 gastritis, and urinary tract infections, or any active diseases, including active
 tuberculosis or a history of active tuberculosis.

 11. Subjects with any acute infection, symptoms suggestive of sinusitis, or significant
 trauma (burns, fractures)

 12. History of malignancy within the past 5 years, other than non-melanoma skin cancer.

 13. History of skeletal muscle myopathy or rhabdomyolysis

 14. Previous exposure to GW856553.

 15. Current use of steroids (inhaled or oral)

 16. Subjects who have donated more than 500 mL of blood within 56 days prior to the study
 medication administration.

 17. Participation in a clinical study where the subject has received a drug or new
 chemical entity within 30 days or 5 half-lives, or twice the duration of the
 biological effect of the drug (whichever is longer) prior to the first dose of study
 medication

 18. History of alcohol/drug abuse or dependence within 12 months of the study

 19. The subject has a three month prior history of regular alcohol consumption exceeding
 an average weekly intake 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

 20. 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.

 21. QTc interval > 450 msec (using average value of triplicate ECGs)

 22. Subjects will be excluded if they have participated in clinical research studies
 involving radiation in the past three years

 23. 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.

 24. 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

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

 Exclusion Criteria for Subjects in MRI Sub-study

 1. 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,

 -  Pacemakers, implantable cardiac defibrillators and non-MR compatible heart
 valves,

 -  Inner ear implants,

 -  History of claustrophobia in MR.

 2. Allergy to MRI contrast enhancement agent (gadolinium).

 3. Serum creatinine clearance < 60 mL/min (At the discretion of the physician, the
 subject may progress to a formal assessment based on 24 hour urine collection should
 serum creatinine limits fall below limits.