Hypercholesterolemia Clinical Trial
Official title:
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Apolipoprotein B(ApoB) Reduction by ISIS 301012 on Liver Triglyceride Content in Subjects With Varying Degrees of Hyperlipidemia
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.
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.
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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