Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3
Condition: Hyperlipidemia
MeSH terms: Hyperlipidemias
Study type: Interventional
Phase: Phase 3

Summary: 
      The primary objective of this study was to evaluate the effect of 24 weeks of evolocumab
      administered subcutaneously (SC) every month, compared with ezetimibe, on low-density
      lipoprotein cholesterol (LDL-C) levels in adults with high cholesterol who are unable to
      tolerate an effective dose of a statin due to muscle-related side effects (MRSE).
    

Detailed description: 
      The study is divided into 3 parts (A, B, C). After an initial 4-week washout period in which
      any statins, ezetimibe, or other lipid-lowering agents were discontinued, participants were
      enrolled in phase A, a double-blind, placebo-controlled crossover procedure to rechallenge
      patients with atorvastatin. Patients were randomly assigned in a 1:1 ratio to receive either
      atorvastatin (20 mg daily) or matching placebo for the first 10 weeks (period 1), then
      underwent a 2-week washout period, followed by crossover to the alternate therapy for a
      second 10-week period (period 2). Patients who experienced intolerable muscle symptoms during
      the first period did not complete the full 10 weeks of exposure but entered a 2-week washout
      period before proceeding to period 2.

      Participants who did not develop muscle-related side effects were removed from the study, as
      were patients who reported muscle-related side effects during a placebo period.

      After completion of phase A, patients who experienced muscle-related adverse effects while
      taking atorvastatin but not placebo were eligible for phase B, a 24-week, double-blind
      randomization to ezetimibe or evolocumab using a double-dummy design in which patients
      received either injectable placebo and oral ezetimibe or injectable evolocumab and oral
      placebo. A patient could proceed directly to phase B if they had a documented history of
      creatine kinase (CK) elevation more than 10 times the upper limit of normal accompanied by
      muscle symptoms while taking statin therapy, with documented resolution of both CK elevation
      and symptoms upon discontinuation of statin therapy.

      These study procedures were designed to ensure that only patients with reproducible
      statin-associated muscle symptoms entered phase B of the study. For phase B, participants
      were randomized 2:1 to receive subcutaneously administered evolocumab (420 mg monthly) or
      oral ezetimibe (10 mg daily). Randomization in part B was stratified by screening LDL-C level
      (< 180 mg/dL [4.66 mmol/L] vs. ≥ 180 mg/dL) at study baseline.

      Participants who completed phase B and did not discontinue SC investigational product for any
      reason, including an adverse event, were eligible to proceed to the 2-year open-label
      extension phase C to evaluate the long-term safety and efficacy of evolocumab in
      statin-intolerant patients. Participants in phase C were allowed to choose quarterly between
      evolocumab 420 mg SC QM or evolocumab 140 mg SC every 2 weeks (Q2W).
    

Intervention name(s): Atorvastatin; Placebo to Atorvastatin; Placebo to Ezetimibe; Ezetimibe; Placebo to Evolocumab; Evolocumab
Intervention type(s): Drug; Drug; Other; Drug; Other; Drug
Intervention description(s): Atorvastatin was supplied as over-encapsulated 20 mg tablets; Placebo matching to atorvastatin supplied as over-encapsulated tablets; Placebo matching to Ezetimibe supplied as over-encapsulated tablets.; Ezetimibe was supplied as 10 mg tablets, over-encapsulated for blinding.; Placebo matching to evolocumab supplied as single-use prefilled autoinjector/pen(s); Evolocumab supplied as single-use prefilled autoinjector/pen(s)
Other intervention name(s): Lipitor; Zetia; Repatha
Intervention MeSH terms: Atorvastatin; Ezetimibe; Evolocumab; Antibodies, Monoclonal
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: High Cholesterol, Treatment for high cholesterol, Lowering cholesterol, Lowering high cholesterol, Hypercholesterolemia