Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration
Condition: Lipid Metabolism, Inborn Errors; Hyperlipidemias; Metabolic Diseases; Hypolipoproteinemia; Hypolipoproteinemias; Hypobetalipoproteinemias; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Congenital Abnormalities; Metabolic Disorder; Hypercholesterolemia; Dyslipidemias; Lipid Metabolism Disorders
MeSH terms: Congenital Abnormalities; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Metabolism, Inborn Errors; Lipid Metabolism, Inborn Errors; Hypobetalipoproteinemias; Hypolipoproteinemias; Hypercholesterolemia; Dyslipidemias; Hyperlipidemias; Hyperlipoproteinemias; Metabolic Diseases; Lipid Metabolism Disorders
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will assess what, if any, effect that ISIS 301012 (mipomersen) has on liver
      triglyceride content in multiple groups of subjects with varying degrees of risk for hepatic
      steatosis. In order to enroll subject groups with varying degrees of risk, the study has
      included multiple cohorts (Cohorts A-G). Additions and removal of cohorts has been
      accomplished with protocol amendments.
    

Detailed description: 
      This was a randomized, double-blind, placebo-controlled study to measure the effect of
      treatment with mipomersen on liver triglyceride (TG) content in patients with varying degrees
      of hyperlipidemia and risk for hepatic steatosis.

      The original study design included 4 cohorts (Cohorts A through D). Subsequent protocol
      amendments added 3 cohorts (Cohorts E, F, and G) to the study, truncated the enrollment of
      Cohort D, and eliminated Cohorts B and C. The study consisted of up to a 3-week screening
      period; a 4-week (Cohorts A and D), 13-week (Cohort E), or 52-week (Cohort G) treatment
      period; and a 20-week post-treatment follow-up period. Cohort F was an observational cohort,
      and therefore, was not treated with study drug. Patients in this cohort underwent a 15-week
      Magnetic resonance spectroscopy (MRS) and ultrasound evaluation period.

      The study cohorts are:

      Cohort A: Healthy volunteers with LDL-C <140 mg/dL (3.6 mmol/L), serum TG <200 mg/dL (2.3
      mmol/L), hemoglobin A1c (HbA1c) <6.0%, and hepatic TG content <5% (as measured by MRS at
      screening). Patients were randomized to mipomersen 200 mg or placebo and treated for 4 weeks.

      Cohorts B+C were eliminated in a protocol amendment prior to enrolling any patients and are
      not discussed further.

      Cohort D: In an amendment to the protocol, Cohort D was closed to enrollment. One patient had
      already been enrolled in the study prior to the amendment. The patient enrolled in this
      cohort had impaired fasting glucose (defined as fasting blood glucose >6 mmol/L and <7
      mmol/L) and mixed dyslipidemia (LDL-C <215 mg/dL [5.6 mmol/L] and serum TG >200 mg/dL [2.3
      mmol/L]). The patient was treated with mipomersen 200 mg for 4 weeks.

      Cohort E: Patients with uncomplicated heterozygous familial hypercholesterolemia (HeFH)
      (Alanine aminotransferase (ALT) ≤1.5 * upper limit of normal Upper limit of normal (ULN), no
      evidence of insulin resistance or metabolic syndrome, and hepatic TG content <5% by MRS at
      screening). Patients were to remain on their baseline statin ± ezetimibe regimen but were to
      wash out from other lipid-lowering agents (e.g., fenofibrate, non-dietary omega-3 fatty
      acids, and niacin) at least 8 weeks prior to the MRS at screening. Patients were randomized
      to either mipomersen 200 mg or placebo for 13 weeks.

      Cohort F: Patients with familial hypobetalipoproteinemia (FHBL) (a documented APOB gene
      mutation that results in the expression of a truncated form of apo B). Patients in this
      cohort were evaluated by MRS, ultrasound, and laboratory tests; however, they were not
      treated with mipomersen or placebo.

      Cohort G: Patients with well-controlled type 2 diabetes mellitus (HbA1c ≤8.0%),
      hypercholesterolemia (LDL-C >100 mg/dL (2.59 mmol/L), and normal serum TG levels (≤200 mg/dL
      [2.26 mmol/L]). Patients were to have been on a stable dose of antidiabetic and
      lipid-lowering medications >3 months prior to screening and were expected to remain stable
      for the duration of the study. Patients were randomized to either mipomersen 200 mg or
      placebo for 26 weeks, followed by 26 additional weeks of mipomersen 200 mg. Recruiting
      difficulties caused this cohort to close early.
    

Intervention name(s): mipomersen; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 200 mg subcutaneous injections; subcutaneous injections
Other intervention name(s): ISIS 301012; mipomersen sodium; Kynamro™
Intervention MeSH terms: Mipomersen
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: LDL-cholesterol; apoB-100; apoB-48; triglyceride; HeFH; FHBL