Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00362180
• Other study ID #: 301012-CS10
• Secondary ID: 2005-005783-90
• Status: Completed
• Phase: Phase 2
• First received: August 7, 2006
• Last updated: June 19, 2015
• Start date: July 2006
• Est. completion date: September 2010

Study information

• Verified date: June 2015
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: Medical Ethics Review Committee (METC)
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 38
• Est. completion date: September 2010
• Est. primary completion date: March 2010
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 65 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Congenital Abnormalities
• Disease
• Dyslipidemias
• Genetic Diseases, Inborn
• Hypercholesterolemia
• Hyperlipidemias
• Hypobetalipoproteinemias
• Hypolipoproteinemia
• Hypolipoproteinemias
• Infant, Newborn, Diseases
• Lipid Metabolism Disorders
• Lipid Metabolism, Inborn Errors
• Metabolic Diseases
• Metabolic Disorder
• Metabolism, Inborn Errors

Intervention

Drug:
• mipomersen
200 mg subcutaneous injections
• Placebo
subcutaneous injections

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company	Ionis Pharmaceuticals, Inc.

Country where clinical trial is conducted

Netherlands, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Liver Triglyceride (TG) Content As Measured by Magnetic Resonance Spectroscopy (MRS)	Localized proton MRS was used to quantify liver TG concentration. All MRS imaging of the liver was performed using the same 1.5T scanner. The instructions were to cover the entire liver (from just above the dome to just below the inferior tip) using a qualified imaging technique (Yokoo, 2009, Radiology). Liver fat quantification was performed by determining the liver fat fraction (%) derived from MRS using selected Regions of Interest (ROI). The analyst typically looked for the branching of the right portal vein and mapped slices from one scan to the next. There were typically 2 ROIs in the right lobe and 1 in the left lobe. Magnetic resonance spectroscopy imaging ROIs between different scans were selected using anatomical landmarks for both time points.	Baseline, Day 26, Day 99	No
Secondary	Baseline Apolipoprotein B	Samples were taken following an overnight fast.	Baseline	No
Secondary	Percent Change in Apolipoprotein B From Baseline to Day 99	Samples were taken following an overnight fast.	Day 26 and Day 99	No
Secondary	Baseline Low-Density Lipoprotein Cholesterol	Samples were taken following overnight fast.	Baseline	No
Secondary	Percent Change in Low-Density Lipoprotein Cholesterol From Baseline to Day 99	Samples were taken following an overnight fast.	Day 26 and Day 99	No
Secondary	Baseline Total Cholesterol	Samples were taken following an overnight fast.	Baseline	No
Secondary	Percent Change in Total Cholesterol From Baseline to Day 99	Samples were taken following an overnight fast.	Day 26 and Day 99	No