Design and Rationale of the <scp>GAUSS</scp>‐2 Study Trial: A Double‐Blind, Ezetimibe‐Controlled Phase 3 Study of the Efficacy and Tolerability of Evolocumab (<scp>AMG</scp> 145) in Subjects With Hypercholesterolemia Who Are Intolerant of Statin Therapy

<jats:title>Abstract</jats:title><jats:p>Statins effectively lower low‐density lipoprotein cholesterol (<jats:styled-content style="fixed-case">LDL</jats:styled-content>‐C), reducing cardiovascular morbidity and mortality. Most patients tolerate statins well, but approximately 10% to 20% experience side effects (primarily muscle‐related) contributing to diminished compliance or discontinuation of statin therapy and subsequent increase in cardiovascular risk. Statin‐intolerant patients require more effective therapies for lowering <jats:styled-content style="fixed-case">LDL</jats:styled-content>‐C. Proprotein convertase subtilisin/kexin type 9 (<jats:styled-content style="fixed-case">PCSK9</jats:styled-content>) is a compelling target for <jats:styled-content style="fixed-case">LDL</jats:styled-content>‐C–lowering therapy. Evolocumab (<jats:styled-content style="fixed-case">AMG</jats:styled-content> 145) is a fully human monoclonal antibody that binds <jats:styled-content style="fixed-case">PCSK9</jats:styled-content>, inhibiting its interaction with the <jats:styled-content style="fixed-case">LDL</jats:styled-content> receptor to preserve <jats:styled-content style="fixed-case">LDL</jats:styled-content>‐receptor recycling and reduce <jats:styled-content style="fixed-case">LDL</jats:styled-content>‐C. Phase 2 studies have demonstrated the safety, tolerability, and preliminary efficacy of subcutaneous evolocumab in diverse populations, including statin‐intolerant patients. This article describes the rationale and design of the Goal Achievement After Utilizing an anti‐<jats:styled-content style="fixed-case">PCSK9</jats:styled-content> Antibody in Statin‐Intolerant Subjects 2 (<jats:styled-content style="fixed-case">GAUSS</jats:styled-content>‐2) trial, a randomized, double‐blind, ezetimibe‐controlled, multicenter phase 3 study to evaluate the effects of 12 weeks of evolocumab 140 mg every 2 weeks or 420 mg every month in statin‐intolerant patients with hypercholesterolemia. Eligible subjects were unable to tolerate effective doses of ≥2 statins because of myalgia, myopathy, myositis, or rhabdomyolysis that resolved with statin discontinuation. The primary objective of the study is to assess the effects of evolocumab on percentage change from baseline in <jats:styled-content style="fixed-case">LDL</jats:styled-content>‐C. Secondary objectives include evaluation of safety and tolerability, comparison of the effects of evolocumab vs ezetimibe on absolute change from baseline in <jats:styled-content style="fixed-case">LDL</jats:styled-content>‐C, and percentage changes from baseline in other lipids. Recruitment of approximately 300 subjects was completed in August 2013.</jats:p>