GW-856553 is under development as a potential anti-atherosclerosis agent for reduction of major cardiovascular events in high risk patient populations. MedDRA version: 9.1 Level: LLT Classification code 10003601 Term: Atherosclerosis
Conditions
Sponsors
GlaxoSmithKline Research & Development Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. 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 either: • experienced a CV event (i.e. acute coronary syndrome, unstable agina, CABG, PCI, stroke, MI, TIA, carotid endarterectomy), but have been clinically stable for at least 6 months since that event [note: if subject with carotid endarterectomy includedtarget vessel for TBR measurement can not be the carotid artery], • or, have peripheral vascular disease (PVD), as indicated by; symptoms of claudication 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 ascending aortic TBR=1.6, as measured on FDG-PET/CT, signifying active inflammation. 5. AST and ALT 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin =65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 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 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. A positive pre-study hepatitis B surface antigen or hepatitis C antibody results within 3 months of screening. 7. Current or chronic history of liver disease, or known hepatic or biliar abnormalities (with the exception of Glibert's syndrome or asymptomatic gallstones). 8.. 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 halfpint (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 va
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To measure in-vivo macrophage activity, by FDG-PET/CT imaging, in carotid arteries and aorta following a 12 week treatment with GW856553 (7.5 mg once daily and 7.5mg twice daily), in the setting of chronic statin therapy, as compared to placebo.; Secondary Objective: • To evaluate the safety and tolerability of 12 weeks of dosing with GW856553 (7.5 mg once daily and 7.5mg twice daily) • To evaluate the effect of 12 weeks of dosing with GW856553, on inflammatory biomarkers. • To determine the effect of short–term p38 inhibition (once daily dosing of 7.5mg GW856553) versus the effect of a 24hr p38 inhibition (twice daily dosing of 7.5 mg GW856553), over a period of 12 weeks, on in-vivo macrophage activity, as assessed by FDG-PET/CT imaging, in the setting of chronic statin therapy. ;Primary end point(s): Change in mean standard uptake values of FDG in aortic and carotid arteries, as assessed by PET/CT (TBR), following 12 weeks of treatment with GW856553 (7.5 mg once daily or 7.5mg twice daily), in the setting of chronic statin therapy, as compared to placebo. | — |
Countries
United Kingdom
Outcome results
None listed