Goal Achievement After Utilizing an Anti-PCSK9 Antibody in Statin Intolerant Subjects-3

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).

Inclusion Criteria:

- Male or female ≥ 18 to ≤ 80 years of age

- Subject not at LDL-C goal

- History of statin intolerance

- Lipid lowering therapy has been stable prior to enrolment for at least 4 weeks

- Fasting triglycerides ≤ 400 mg/dL

Exclusion Criteria:

- New York Heart Association (NYHA) III or IV heart failure

- Uncontrolled cardiac arrhythmia

- Uncontrolled hypertension

- Type 1 diabetes

- Poorly controlled type 2 diabetes

- Uncontrolled hypothyroidism or hyperthyroidism