a study of the safety and efficacy of two different regimens of mipomersen in patients with familial hypercholesterolemia and inadequately controlled low-density lipoprotein cholesterol

Conditions: Hypercholesterolemia; Heterozygous Familial

Summary: primary objective: determine whether mipomersen (isis 301012) significantly reduces atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (severe hefh), defined as low-density lipoprotein cholesterol (ldl-c) levels ≥200 mg/dl plus the presence of coronary heart disease (chd)/risk equivalents or ldl-c levels ≥300 mg/dl regardless of the presence of chd/risk equivalents (referred to as cohort 1) compared to placebo. two different mipomersen dosing regimens will be studied: subcutaneous (sc) mipomersen 200 mg once weekly versus placebo, and sc mipomersen 70 mg thrice weekly versus placebo. secondary objectives: * determine whether there are qualitative differences between the safety profiles of the 2 dosing regimens and placebo in cohort 1, patients with hefh with ldl-c levels ≥160 mg/dl and \<200 mg/dl plus the presence of chd/risk equivalents (referred to as cohort 2), and the overall study population * determine whether there are qualitative differences between the tolerability of the 2 dosing regimens and placebo in cohort 1, cohort 2, and the overall study population * further characterize the pharmacokinetics (pk) of the 2 dosing regimens in cohort 1, cohort 2, and the overall study population * determine whether the 2 mipomersen dosing regimens significantly reduce atherogenic lipid levels in cohort 2 compared to placebo * obtain additional data regarding ongoing safety and efficacy of mipomersen in patients with fh and inadequately controlled ldl-c who complete the primary efficacy assessment visit (pet) in the blinded treatment period and continue treatment in open-label continuation period

the study consisted of a screening period of up to 4 weeks, blinded treatment phase of 60 weeks, open-label continuation period of 26 weeks, and post-treatment phase of 24 weeks. study design, masking - study treatment was blinded (double-blinded) through the primary efficacy assessment visit in the blinded treatment period. study treatment was open-label in the open-label continuation period.

Eligibility criteria:
inclusion criteria: * diagnosis of severe hypercholesterolemia (ldl-c ≥300 mg/dl (7.77 mmol/l) or ldl-c ≥200 mg/dl (5.18 mmol/l) with documented coronary heart disease (chd) or chd risk equivalents, or diagnosis of heterozygous familial hypercholesterolemia and ldl-c ≥160 mg/dl (4.14 mmol/l) and \<200 mg/dl (5.18 mmol/l)) * on stable, maximally tolerated, statin therapy for at least 12 weeks or if statin intolerant, on at least 1 medication from another class of hypolipidemic agents (i.e., bile acid sequestrants, niacin/nicotinic acid, cholesterol absorption inhibitors, fibrates). * on stable, low fat diet for 12 weeks * body mass index (bmi) ≤40 kg/m2 and stable weight for \> 6 weeks exclusion criteria: * significant health problems in the recent past including heart attack, stroke, coronary syndrome, unstable angina, heart failure, significant arrhythmia, hypertension, blood disorders, liver disease, cancer, digestive disorders, type i diabetes, or uncontrolled type ii diabetes * apheresis within 3 months prior to screening or expected to start apheresis during the treatment phase