Double-blind, Randomized, Multicenter, Placebo-controlled, Parallel Group Study to Characterize the Efficacy, Safety, and Tolerability of 24 Weeks of Evolocumab for Low Density Lipoprotein-cholesterol (LDL-C) Reduction, as Add-On to Diet and Lipid-Lowering Therapy, in Pediatric Subjects 10 to 17 Years of Age With Heterozygous Familial Hypercholesterolemia (HeFH)

Hypercholesterolemia (elevated serum low-density lipoprotein cholesterol
[LDL-C]) is an established risk factor for coronary heart disease (CHD) in
humans (Grundy et al, 2004), and more than 50 million patients are treated for
hypercholesterolemia in the United States and Europe (Kuklina et al, 2011;
Kotseva et al, 2009; Tolonen et al, 2005).
Cholesterol elevations requiring pharmacologic therapy are uncommon in
children. However, patients with familial hypercholesterolemia (FH), an almost
exclusively autosomal dominant condition most often resulting from deficient or
defective LDLR function (Rader et al, 2003), have elevated LDL-C beginning in
childhood. Since FH is a genetic condition, the prevalence among children is
very similar to the prevalence among younger adults. In the pediatric
population, FH may be identified by the combination of elevated LDL-C and a
positive family history of hypercholesterolemia and/or premature cardiovascular
disease. HeFH affects approximately one out of every 200 to 500 people
worldwide (National Collaborating Centre, 2008; Nordestgaard et al, 2013; Rader
et al, 2003). By comparison, HoFH is present in approximately 1 in 1,000,000
individuals (Goldstein et al, 2001). Without treatment, these patients have
severe hypercholesterolemia, develop premature coronary artery disease, and are
at increased risk for premature cardiovascular death (Rader et al, 2003). In
the adult population, hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase
inhibitors (statins) are currently the treatment of choice for both
heterozygous FH patients and homozygous FH patients (Grundy et al, 2004), as
statins inhibit endogenous cholesterol biosynthesis and upregulate LDLR
expression (increasing the activity of functional LDLR) (Rader et al, 2003).
Although statins reduce mortality in this patient population (Raal et al,
2011), cholesterol levels may remain elevated in FH patients despite therapy
with diet, exercise, and medications.
Pediatric guidelines in the United States (Daniels and Greer, 2008;McCrindle et
al, 2007; Kavey et al, 2006) recommend considering pharmacologic
treatment after initial treatment with lifestyle modification has failed in
patients >= 10 years of age with LDL-C that is:
* >= 130 mg/dL (3.4 mmol/L) for the highest risk (eg, diabetes mellitus)
* >= 160 mg/dL (4.1 mmol/L) for intermediate risk (eg, >= 2 other CHD risk
factors,
family history of premature coronary artery disease [CAD])
* >= 190 mg/dL (4.9 mmol/L) for the lowest risk (no cardiovascular risk factors)
Similarly, treatment guidelines from the European Society of Cardiology and
European Atherosclerosis Society (ESC/EAS; Reiner et al, 2011) and from the
National Institute for Health and Clinical Excellence (NICE; National
Collaborating Centre, 2008) recommend statin treatment in patients who are >= 10
years of age and have HeFH or HoFH, and consider pharmacologic treatment for
subjects with HoFH at earlier ages (Reiner et al, 2011). When a child with FH
has exceptionally high LDL-C and/or cardiovascular risk, bile acid sequestrants
and ezetimibe are also indicated and may be used in combination. Thus, while
currently available therapies can reduce LDL-C levels, novel therapies that can
be used alone or in combination with existing agents to more effectively reduce
LDL-C would be valuable for both adults and pediatric patients with severely
elevated cholesterol levels.

To evaluate the effect of 24 weeks of subcutaneous (SC) evolocumab compared
with placebo, when added to standard of care, on percent change from baseline
in low-density lipoprotein cholesterol (LDL-C) in pediatric subjects 10 to 17
years of age with HeFH.

This is a randomized, multicenter, placebo-controlled, double-blind, parallel
group study. Subjects are eligible for screening if they are 10 to 17 years of
age at time of randomization and have met the local applicable diagnostic
criteria for HeFH. Subjects considered for enrollment will undergo screening
assessments, including laboratory screening by central laboratory.
Approximately 150 eligible subjects will be randomized in a 2:1 ratio to
receive 24 weeks of QM evolocumab or placebo. Randomization will be stratified
by screening LDL-C (< 160 mg/dL [4.1 mmol/L] vs >= 160 mg/dL) and age (< 14
years vs >= 14 years).
The study includes collection of biomarker development samples. Where permitted
by local regulations, subjects will be invited to consent to pharmacogenetic
analyses.
After completion of Study 20120123, subjects will be offered to participate in
an extension study where they will receive open-label evolocumab.

Subjects being considered for participation in this study, and who have signed
informed consent or subject assent, will be assessed for inclusion and
exclusion criteria. Medical and medication history will be obtained. Subjects
will undergo screening assessments, including a SC administration of placebo to
evaluate tolerability of the SC injection via the prefilled AI/pen. Lipid
eligibility screening must be conducted after the subject has been on a low-fat
diet and receiving lipid lowering therapy that includes an optimal dose of a
statin not requiring uptitration in the opinion of the investigator and has
been stable for >= 4 weeks. Subjects should maintain their diet, lipid-lowering
therapy, and exercise regimen unchanged throughout screening and all phases of
study participation. Eligible subjects will be randomized to receive IP
(evolocumab or
placebo), in addition to their background lipid lowering therapy. An
interactive voice response system and/or interactive web response system
(IVRS/IWRS) will allocate subjects to administration of investigational
product. Day 1 is defined as the day of first administration of
investigational product. Subsequent study visits are at weeks 4, 12, 20, 22,
and 24 (EOS, end-of-study). Day 1 and week 24 visits must be scheduled at
approximately the same time of day, and should be performed as close as
possible to 8 am as the hormones measured have
diurnal variation. IP administration is every 4 weeks. Administration at weeks
8 and 16 can be at the study site (optional visit) or at a location other than
the study site. Last administration of IP is at week 20. Subjects who
discontinue IP early for any reason will be asked to continue to return
for all other study procedures and measurements until the end of the study.
Assessments and procedures include vital signs, adverse events/serious adverse
events/adverse device effects (ADE)/disease related events(DRE)/cardiovascular
(CV) events, and concomitant therapy, dietary instruction, physical exam
including neurologic examination and assessment of waist circumference, body
height and weight, 12-lead electrocardiograms (ECGs), fasting lipids,
chemistry, hematology, anti-evolocumab antibodies, biomarker sample collection,
serum pregnancy testing (females of childbearing potential), urinalysis,
assessment of growth and pubertal development (Tanner staging), Cogstate
neurocognitive assessment, carotid intima-media thickness (cIMT), and IP
administration. In
addition, specific laboratory assessments will be performed, including
estradiol for girls, testosterone for boys, creatinine phosphokinase,
follicle-stimulating hormone, luteinizing hormone, adenocorticotropic hormone,
dehydroepiandrosterone, and cortisol. If the subject consented to
pharmacogenetics analyses, DNA will be extracted from some of the blood
samples. IP administration by SC injection, if applicable, will be done after
all other procedures have been completed.

Subjects will have more visits to the hospital; risks associated with
participation are the one linked to the investigational product.