Clinical trial NCT00362180: Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
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
Lead sponsor: Kastle Therapeutics, LLC
Sponsor class: INDUSTRY
Collaborators: name: Ionis Pharmaceuticals, Inc.
First posted: 2006-08-09
Enrollment: 38
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

* Group A - are healthy subjects
* Group D - has impaired fasting glucose and mixed dyslipidemia
* Group E - has a diagnosis of Heterozygous Familial Hypercholesterolemia (HeFH) and on stable lipid-lowering therapy for 3 months
* Group F - has a diagnosis of Familial Hypobetalipoproteinemia (FHBL)
* Group G - has a diagnosis of Diabetes and hypercholesterolemia

Exclusion Criteria:

* Medical, surgical, laboratory or other conditions which in the judgment of the Physician Investigator would make the subject unsuitable for enrollment, or potentially interfere with subject participation or completion of the study.

Primary outcomes:
measure: Change From Baseline in Liver Triglyceride (TG) Content As Measured by Magnetic Resonance Spectroscopy (MRS)
timeFrame: Baseline, Day 26, Day 99
Secondary outcomes:
measure: Baseline Apolipoprotein B
timeFrame: Baseline
measure: Percent Change in Apolipoprotein B From Baseline to Day 99
timeFrame: Day 26 and Day 99
measure: Baseline Low-Density Lipoprotein Cholesterol
timeFrame: Baseline
measure: Percent Change in Low-Density Lipoprotein Cholesterol From Baseline to Day 99
timeFrame: Day 26 and Day 99
measure: Baseline Total Cholesterol
timeFrame: Baseline
measure: Percent Change in Total Cholesterol From Baseline to Day 99
timeFrame: Day 26 and Day 99
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Visser ME, Akdim F, Tribble DL, Nederveen AJ, Kwoh TJ, Kastelein JJ, Trip MD, Stroes ES. Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia. J Lipid Res. 2010 May;51(5):1057-62. doi: 10.1194/jlr.M002915. Epub 2009 Dec 14.