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
Condition: Hypercholesterolemia; Heterozygous Familial
MeSH terms: Hyperlipoproteinemia Type II; Hypercholesterolemia
Intervention: mipomersen sodium 200 mg; Placebo; mipomersen sodium 70 mg
Intervention description: Subcutaneous mipomersen 200 mg once weekly; Placebo vehicle for subcutaneous injection.; Subcutaneous mipomersen 70 mg thrice weekly
Intervention MeSH terms: Mipomersen
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 309.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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
    

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