Optimal dichotomization for repeated screening tests

Repeated use of a screening test for ascertaining a characteristic often can improve screening performance. We propose a Bayesian predictive decision-theoretic approach to choosing an optimal dichotomizer for the screening test variable in the repeat-test setting.Screening test Repeated testing Optimal dichotomizer Bayesian predictive decision-theoretic approach Monte Carlo optimization

Safety and efficacy of LY3015014, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9): a randomized, placebo-controlled Phase 2 study

Aims The objective of this study was to evaluate the efficacy, safety, and tolerability of LY3015014 (LY), a neutralizing antibody of proprotein convertase subtilisin/kexin type 9 (PCSK9), administered every 4 or 8 weeks in patients with primary hypercholesterolaemia, when added to a background of standard-of-care lipid-lowering therapy, including statins. Methods and results Double-blind, placebo-controlled trial randomized 527 patients with primary hypercholesterolaemia from June 2013 to January 2014 at 61 community and academic centres in North America, Europe, and Japan. Patients were randomized to subcutaneous injections of LY 20, 120, or 300 mg every 4 weeks (Q4W); 100 or 300 mg every 8 weeks (Q8W) alternating with placebo Q4W; or placebo Q4W. The primary endpoint was percentage change from baseline in low-density lipoprotein cholesterol (LDL-C) by beta quantification at Week 16. The mean baseline LDL-C by beta quantification was 136.3 (SD, 45.0) mg/dL. LY3015014 dose-dependently decreased LDL-C, with a maximal reduction of 50.5% with 300 mg LY Q4W and 37.1% with 300 mg LY Q8W compared with a 7.6% increase with placebo maintained at the end of the dosing interval. There were no treatment-related serious adverse events (AEs). The most common AE terms (>10% of any treatment group) reported more frequently with LY compared with placebo were injection site (IS) pain and IS erythema. No liver or muscle safety issues emerged. Conclusions LY3015014 dosed every 4 or 8 weeks, resulted in robust and durable reductions in LDL-C. No clinically relevant safety issues emerged with the administration of LY. The long-term effects on cardiovascular outcomes require further investigatio

Effects of the CETP inhibitor evacetrapib administered as monotherapy or in combination with statins on HDL and LDL cholesterol: a randomized controlled trial

Interest remains high in cholesteryl ester transfer protein (CETP) inhibitors as cardioprotective agents. Few studies have documented the efficacy and safety of CETP inhibitors in combination with commonly used statins. To examine the biochemical effects, safety, and tolerability of evacetrapib, as monotherapy and in combination with statins, in patients with dyslipidemia. Randomized controlled trial conducted among 398 patients with elevated low-density lipoprotein cholesterol (LDL-C) or low high-density lipoprotein cholesterol (HDL-C) levels from April 2010 to January 2011 at community and academic centers in the United States and Europe. Following dietary lead-in, patients were randomly assigned to receive placebo (n = 38); evacetrapib monotherapy, 30 mg/d (n = 40), 100 mg/d (n = 39), or 500 mg/d (n = 42); or statin therapy (n = 239) (simvastatin, 40 mg/d; atorvastatin, 20 mg/d; or rosuvastatin, 10 mg/d) with or without evacetrapib, 100 mg/d, for 12 weeks. The co-primary end points were percentage changes from baseline in HDL-C and LDL-C after 12 weeks of treatment. The mean baseline HDL-C level was 55.1 (SD, 15.3) mg/dL and the mean baseline LDL-C level was 144.3 (SD, 26.6) mg/dL. As monotherapy, evacetrapib produced dose-dependent increases in HDL-C of 30.0 to 66.0 mg/dL (53.6% to 128.8%) compared with a decrease with placebo of -0.7 mg/dL (-3.0%; P < .001 for all compared with placebo) and decreases in LDL-C of -20.5 to -51.4 mg/dL (-13.6% to -35.9%) compared with an increase with placebo of 7.2 mg/dL (3.9%; P < .001 for all compared with placebo). In combination with statin therapy, evacetrapib, 100 mg/d, produced increases in HDL-C of 42.1 to 50.5 mg/dL (78.5% to 88.5%; P < .001 for all compared with statin monotherapy) and decreases in LDL-C of -67.1 to -75.8 mg/dL (-11.2% to -13.9%; P < .001 for all compared with statin monotherapy). Compared with evacetrapib monotherapy, the combination of statins and evacetrapib resulted in greater reductions in LDL-C (P <.001) but no greater increase in HDL-C (P =.39). Although the study was underpowered, no adverse effects were observed. Compared with placebo or statin monotherapy, evacetrapib as monotherapy or in combination with statins increased HDL-C levels and decreased LDL-C levels. The effects on cardiovascular outcomes require further investigation. clinicaltrials.gov Identifier: NCT0110597

Potent and selective PPAR-alpha agonist LY518674 upregulates both ApoA-I production and catabolism in human subjects with the metabolic syndrome.

OBJECTIVE: The study of PPAR-alpha activation on apoA-I production in humans has been limited to fibrates, relatively weak PPAR-alpha agonists that may have other molecular effects. We sought to determine the effect of a potent and highly specific PPAR-alpha agonist, LY518674, on apoA-I, apoA-II, and apoB-100 kinetics in humans with metabolic syndrome and low levels of HDL cholesterol (C). METHODS AND RESULTS: Subjects were randomized to receive LY518674 (100 microg) once daily (n=13) or placebo (n=15) for 8 weeks. Subjects underwent a kinetic study using a deuterated leucine tracer to measure apolipoprotein production and fractional catabolic rates (FCR) at baseline and after treatment. LY518674 significantly reduced VLDL-C (-38%, P=0.002) and triglyceride (-23%, P=0.002) levels whereas LDL-C and HDL-C levels were unchanged. LY518674 significantly reduced VLDL apoB-100 (-12%, P=0.01) levels, attributable to an increased VLDL apoB-100 FCR with no change in VLDL apoB-100 production. IDL and LDL apoB-100 kinetics were unchanged. LY518674 significantly increased the apoA-I production rate by 31% (P CONCLUSIONS: Activation of PPAR-alpha with LY518674 (100 microg) in subjects with metabolic syndrome and low HDL-C increased the VLDL apoB-100 FCR consistent with enhanced lipolysis of plasma triglyceride. Significant increases in the apoA-I and apoA-II production rates were accompanied by increased FCRs resulting in no change in HDL-C levels. These data indicate a major effect of LY518674 on the production and clearance of apoA-I and HDL despite no change in the plasma concentration. The effect of these changes on reverse cholesterol transport remains to be determined