Rationale and design of LAPLACE-2: a phase 3, randomized, double-blind, placebo- and ezetimibe-controlled trial evaluating the efficacy and safety of evolocumab in subjects with hypercholesterolemia on background statin therapy

Abstract

Low-density lipoprotein cholesterol (LDL-C) levels are significantly associated with atherosclerotic cardiovascular disease (ASCVD) risk, and studies using interventions that lower LDL-C levels have been shown to reduce the risk of ASCVD events and mortality. Statin treatment is the current first-line therapy for lowering LDL-C and reducing ASCVD risk. However, many patients are still unable to reach recommended LDL-C goals on maximally tolerated statin therapy. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9, including evolocumab (previously AMG 145), dramatically lowered LDL-C in phase 2 clinical trials when administered alone or in combination with a statin. The aim of this phase 3 study is to evaluate the efficacy of 12 weeks of subcutaneous evolocumab (vs placebo) administered every 2 weeks or every month in combination with a statin in patients with hypercholesterolemia and mixed dyslipidemia. This study will also provide comparative efficacy, safety, and tolerability data between evolocumab and ezetimibe when added to background atorvastatin therapy.

Figure 1

Treatment schema. Subjects who fulfilled the inclusion/exclusion criteria and completed the placebo run‐in period were assigned to 1 of 5 statin treatment arms. Following 4 weeks of stable lipid therapy, subjects were randomized to evolocumab, placebo, or ezetimibe (atorvastatin treatment arms only). Evolocumab Q2W dosage was 140 mg; evolocumab QM dose was 420 mg. Administration of study drug is indicated with a vertical arrow. Results are based on a data cut taken September 23, 2013. Abbreviations: CrCl, creatinine clearance; IP, investigational product; LDL‐C, low‐density lipoprotein cholesterol; PO, oral; Q2W, every 2 weeks; QM, every month; SAE, serious adverse event; SC, subcutaneous; W, week. ^a Subjects with moderate renal impairment (CrCl <60 mL/min) and Asian subjects who were randomized to the rosuvastatin maximum‐dose arm received rosuvastatin 20 mg. ^b Subjects randomized to simvastatin and on contraindicated therapies were assigned a lower dose (either 10 or 20 mg). ^c Phone call for SAEs for subjects receiving SC IP administration Q2W.