SB-480848 is under developement as a potential anti-atherosclerosis agent for reduction of major cardiovascular events in high risk patient populations.
Conditions
Sponsors
GlaxoSmithKline Research & Development Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Signed written informed consent prior to beginning study-related procedures (subject must understand the aims, investigational procedures and possible consequences of the study). 2. Male or female aged 18 to 80 years of age at screening. Female subjects of childbearing potential must be willing to follow contraceptive measures (described in Appendix 3 of study protocol). 3. Successful percutaneous coronary intervention (PCI) defined as placement of bare metal or drug eluting stent in the native coronary arteries or Uncomplicated diagnostic cardiac catheterization in subjects in whom no PCI is planned. Important: approximately =50% of randomized subjects must present with ACS and evidence of myocardial necrosis (i.e., STEMI or NSTEMI). ACS is defined as a history of chest pain (or chest pain equivalent) lasting = 20 minutes that occurred within 72 hours prior to the qualifying IVUS and the presence of elevated concentrations of cardiac biomarkers (troponins). Pre-catheterization Troponin must be assessed at both central and local laboratories and determined to be >99th percentile of the values for a reference control group to qualify as evidence of myocardial necrosis. The central laboratory Troponin I value will be used for the purpose of analyses. 4. Baseline IVUS of the non-intervened coronary arterial segment recorded according to protocol-mandated criteria that contains a lesion with less than 50% stenosis by visual inspection on angiography (refer to IBIS-2 Study Manual: – Imaging Procedures and Measurements [Core Imaging Laboratory, 2005]) 5. Must be receiving at least one oral antiplatelet agent (e.g., aspirin, clopidogrel) at time of randomization. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: Clinical and laboratory exclusion criteria: 1. Evidence of clinical instability or new abnormal clinical laboratory findings post-PCI or post cardiac catheterization but prior to randomization that in opinion of the investigator makes the subject unsuitable for the study. 2. History of CABG surgery. 3. Planned cardiac surgery (e.g., CABG, valve repair or replacement) or planned major non-cardiac surgery within the study period. 4. Stroke or resuscitated cardiac arrest in the past 6 months. 5. QTc interval >440msec (males) or >450msec (females) at Screening 6. History of chronic viral hepatitis (including hepatitis B surface antigen or hepatitis C antibody) or other chronic hepatic disorder. ALT or AST >2.5 x upper limit of normal or alkaline phosphatase or total bilirubin >1.5 x upper limit of normal at Screening. 7. Renal impairment with serum creatinine >2.0 mg/dL (177umol/L) or calculated creatinine clearance 160 mmHg systolic and/or >100 mmHg diastolic) on a stable dose of antihypertensive medication. 9. Recent use (within 10% at Screen. 11. History of severe heart failure defined as NYHA class III or IV or known severe left ventricular (LV) dysfunction (ejection fraction [EF] 240mL daily of grapefruit-juice, which may inhibit CYP3A4. 18. Previous exposure to SB-480848. 19. Use of an investigational device or investigational drug within 30 days or 5 half-lives (whichever is the longer) preceding the first dose of study medication. 20. Pregnancy (defined as a positive pregnancy test by serum ß-HCG) or lactation at Screening. 21. Any subject the investigator deems unsuitable for the study (e.g., due to medical reasons, laboratory abnormalities, expected study medication noncompliance, or unwillingness or inability to comply with all study-related procedures). Anatomical exclusion criter
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To examine, in an exploratory fashion, whether SB-480848 provides measurable benefit on intermediate CV endpoints (plasma hsCRP levels and the density of high strain spots in the non-intervened segment of coronary arteries characterized by palpography) following 52 weeks of treatment.; Secondary Objective: Biomarkers: • examine effects of SB-480848 on an array of circulating markers of inflammatory burden (IL-6, ICAM-1, sCD40L, MPO) and plaque instability (MMP-9) at 26 and 52 weeks of treatment. • examine effects of SB-480848 on plasma Lp-PLA2 activity and Lp-PLA2 target-related biomarkers (Lyso-PC, ox-NEFA and ox-LDL) at 26 and 52 weeks of treatment. Imaging: • determine the effects of SB-480848 on compositional and volumetric measures of coronary plaque and volumetric measures of vessel and lumen in non-intervened coronary segment measured by IVUS at 52 weeks of treatment. Endothelial function: • determine effects of SB-480848 on measures of endothelial function at 4, 13, 26 and 52 weeks of treatment. Safety: • assess safety and tolerability of SB-480848 over a 52 week treatment period. • examine effects of SB-480848 on the first occurrence of the components of the composite measure of MACE (Major Adverse Cardiovascular Events) over 12 months of treatment. ; Primary end point(s): The study will have two co-primary endpoints in order to assess intermediate cardiovascular (CV) endpoints. They will include: - on-treatment differences between SB-480848 and placebo treated groups in circulating hsCRP levels following 52 weeks of treatment, and - the differences between SB-480848 and placebo treated groups in baseline-corrected density of Rotterdam Classification (ROC) grade III/IV strain spots/10mm within the region of in | — |
Countries
Austria, Czech Republic, Denmark, Germany, Spain, United Kingdom
Outcome results
None listed