Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration

This study has been completed.
Sponsor:
Collaborator:
Isis Pharmaceuticals
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier:
NCT00362180
First received: August 7, 2006
Last updated: June 19, 2015
Last verified: June 2015
  Purpose

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.


Condition Intervention Phase
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
Drug: mipomersen
Drug: Placebo
Phase 2

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

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Change From Baseline in Liver Triglyceride (TG) Content As Measured by Magnetic Resonance Spectroscopy (MRS) [ Time Frame: Baseline, Day 26, Day 99 ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Baseline Apolipoprotein B [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Samples were taken following an overnight fast.

  • Percent Change in Apolipoprotein B From Baseline to Day 99 [ Time Frame: Day 26 and Day 99 ] [ Designated as safety issue: No ]
    Samples were taken following an overnight fast.

  • Baseline Low-Density Lipoprotein Cholesterol [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Samples were taken following overnight fast.

  • Percent Change in Low-Density Lipoprotein Cholesterol From Baseline to Day 99 [ Time Frame: Day 26 and Day 99 ] [ Designated as safety issue: No ]
    Samples were taken following an overnight fast.

  • Baseline Total Cholesterol [ Time Frame: Baseline ] [ Designated as safety issue: No ]
    Samples were taken following an overnight fast.

  • Percent Change in Total Cholesterol From Baseline to Day 99 [ Time Frame: Day 26 and Day 99 ] [ Designated as safety issue: No ]
    Samples were taken following an overnight fast.


Enrollment: 38
Study Start Date: July 2006
Study Completion Date: September 2010
Primary Completion Date: March 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort A: mipomersen
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.
Drug: mipomersen
200 mg subcutaneous injections
Other Names:
  • ISIS 301012
  • mipomersen sodium
  • Kynamro™
Placebo Comparator: Cohort A: placebo
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.
Drug: Placebo
subcutaneous injections
Other Name: placebo
Experimental: Cohort D: mipomersen
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.
Drug: mipomersen
200 mg subcutaneous injections
Other Names:
  • ISIS 301012
  • mipomersen sodium
  • Kynamro™
Placebo Comparator: Cohort D: placebo
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.
Drug: Placebo
subcutaneous injections
Other Name: placebo
Experimental: Cohort E: mipomersen
Participants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly mipomersen 200 mg injections for 13 weeks.
Drug: mipomersen
200 mg subcutaneous injections
Other Names:
  • ISIS 301012
  • mipomersen sodium
  • Kynamro™
Placebo Comparator: Cohort E: placebo
Participants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly placebo injections for 13 weeks.
Drug: Placebo
subcutaneous injections
Other Name: placebo
No Intervention: Cohort F: no intervention
A reference group of participants with familial hypobetalipoproteinemia (FBHL) who did not receive a study intervention. Data gathered for 15 weeks.
Experimental: Cohort G: mipomersen
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.
Drug: mipomersen
200 mg subcutaneous injections
Other Names:
  • ISIS 301012
  • mipomersen sodium
  • Kynamro™
Placebo Comparator: Cohort G: placebo followed by mipomersen
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.
Drug: mipomersen
200 mg subcutaneous injections
Other Names:
  • ISIS 301012
  • mipomersen sodium
  • Kynamro™
Drug: Placebo
subcutaneous injections
Other Name: placebo

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

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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.
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00362180

Locations
Netherlands
Amsterdam, Netherlands, 1105 AZ
Sponsors and Collaborators
Genzyme, a Sanofi Company
Isis Pharmaceuticals
Investigators
Study Director: Medical Monitor Genzyme, a Sanofi Company
  More Information

Publications:
Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier: NCT00362180     History of Changes
Other Study ID Numbers: 301012-CS10, 2005-005783-90
Study First Received: August 7, 2006
Results First Received: February 25, 2013
Last Updated: June 19, 2015
Health Authority: Netherlands: Medical Ethics Review Committee (METC)

Keywords provided by Sanofi:
LDL-cholesterol
apoB-100
apoB-48
triglyceride
HeFH
FHBL

Additional relevant MeSH terms:
Hypobetalipoproteinemias
Congenital Abnormalities
Dyslipidemias
Genetic Diseases, Inborn
Hypercholesterolemia
Hyperlipidemias
Hypolipoproteinemias
Infant, Newborn, Diseases
Lipid Metabolism Disorders
Lipid Metabolism, Inborn Errors
Metabolic Diseases
Metabolism, Inborn Errors
Sphingolipidoses
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Lipidoses
Lysosomal Storage Diseases
Lysosomal Storage Diseases, Nervous System
Nervous System Diseases
Mipomersen
Anticholesteremic Agents
Antimetabolites
Diagnostic Uses of Chemicals
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Molecular Probes
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 30, 2015