Clinical trial NCT00362180
Conditions: 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
Keywords: LDL-cholesterol apoB-100 apoB-48 triglyceride HeFH FHBL
Sponsor: Kastle Therapeutics, LLC
Start date: 2006-07-01; Completion date: 2010-09-01
Enrollment: 38 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief 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.

Arms: arm 1: Healthy volunteers treated with 6 injections of mipomersen 200 mg over the course of 4 weeks. Injections were given subcutaneously (sc) on days 1, 4, 8, 11, 15 and 22. arm 2: Healthy volunteers treated with 6 injections of placebo over the course of 4 weeks. Injections were given subcutaneously (sc) on days 1, 4, 8, 11, 15 and 22. arm 3: Participants with impaired fasting glucose and mixed dyslipidemia who were treated with 6 injections of mipomersen 200 mg over the course of 4 weeks. Injections were given subcutaneously (sc) on days 1, 4, 8, 11, 15 and 22. arm 4: Participants with impaired fasting glucose and mixed dyslipidemia who were treated with 6 injections of placebo over the course of 4 weeks. Injections were given subcutaneously (sc) on days 1, 4, 8, 11, 15 and 22. arm 5: Participants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly mipomersen 200 mg injections for 13 weeks. arm 6: Participants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly placebo injections for 13 weeks. arm 7: A reference group of participants with familial hypobetalipoproteinemia (FBHL) who did not receive a study intervention. Data gathered for 15 weeks. arm 8: Participants with well-controlled Type 2 diabetes mellitus, hypercholesterolemia, and normal triglyceride levels were treated with mipomersen 200 mg weekly for 26 weeks, followed by open-label mipomersen 200 mg weekly for an additional 26 weeks. arm 9: Participants with well-controlled Type 2 diabetes mellitus, hypercholesterolemia, and normal triglyceride levels were treated with placebo weekly for 26 weeks, followed by open-label mipomersen 200 mg weekly for an additional 26 weeks.
Interventions: intervention 1: mipomersen intervention 2: Placebo
Intervention descriptions: intervention 1: 200 mg subcutaneous injections intervention 2: subcutaneous injections

Protocol documents: