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Background  The aim of this study was to assess the effects of darapladib, a selective oral investigational lipoprotein-associated phospholipase A 2  inhibitor, on both plasma and plaque lipoprotein-associated phospholipase A 2  activity.    Methods  Patients undergoing elective carotid endarterectomy were randomized to darapladib 40 mg (n = 34), 80 mg (n = 34), or placebo (n = 34) for 14 days, followed by carotid endarterectomy 24 hours after the last dose of study medication.    Results  Darapladib 40 mg and 80 mg reduced plasma lipoprotein-associated phospholipase A 2  activity by 52% and 81%, respectively, versus placebo (both  P <0.001). Significant reductions in plaque lipoprotein-associated phospholipase A 2  activity were also observed compared with placebo ( P <0.0001), which equated to a 52% and 80% decrease compared with placebo. No significant differences were observed between groups in plaque lysophosphatidylcholine content or other biomarkers, although a dose-dependent decrease in plaque matrix metalloproteinase-9 mRNA expression was observed with darapladib 80 mg ( P  = 0.053 vs placebo). In a post-hoc analysis, plaque caspase-3 ( P <0.001) and caspase-8 ( P <0.05) activity were found to be significantly lower in the darapladib 80-mg group versus placebo. No major safety concerns were identified in the study.    Conclusions  Short-term treatment (14±4 days) with darapladib produced a robust, dose-dependent reduction in plasma lipoprotein-associated phospholipase A 2  activity. More importantly, darapladib demonstrated placebo-corrected reductions in carotid plaque lipoprotein-associated phospholipase A 2  activity of similar magnitude. Darapladib was generally well tolerated and no safety concerns were identified. Additional studies of longer duration are needed to explore whether these pharmacodynamic effects are associated with improved clinical outcomes, as might be hypothesized.    Trial Registration Information  Name of Registry 1: ClinicalTrials.gov  Registry Number 1: NCT01916720  Trial URL in Registry Database 1:  www.clinicaltrials.gov/ct2/show/NCT01916720    Name of Registry 2: GSK Clinical Study Register  Registry Number 2∶480848/010  Trial URL in Registry Database 2:  www.gsk-clinicalstudyregister.com/result_detail.jsp?protocolId=480848%2F010&studyId=74F5DB65-4661-4FA8-91D4-EBF78D769F24&compound=darapladib&type=Compound&letterrange=A-F

Effect of Darapladib Treatment on Endarterectomy Carotid Plaque Lipoprotein-Associated Phospholipase A2 Activity: A Randomized, Controlled Trial