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Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration

Primary Purpose

Lipid Metabolism, Inborn Errors, Hyperlipidemias, Metabolic Diseases

Status
Completed
Phase
Phase 2
Locations
Netherlands
Study Type
Interventional
Intervention
mipomersen
Placebo
Sponsored by
Kastle Therapeutics, LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lipid Metabolism, Inborn Errors focused on measuring LDL-cholesterol, apoB-100, apoB-48, triglyceride, HeFH, FHBL

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesAccepts Healthy Volunteers

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.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Experimental

Placebo Comparator

No Intervention

Experimental

Placebo Comparator

Arm Label

Cohort A: mipomersen

Cohort A: placebo

Cohort D: mipomersen

Cohort D: placebo

Cohort E: mipomersen

Cohort E: placebo

Cohort F: no intervention

Cohort G: mipomersen

Cohort G: placebo followed by mipomersen

Arm Description

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.

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.

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.

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.

Participants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly mipomersen 200 mg injections for 13 weeks.

Participants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly placebo injections for 13 weeks.

A reference group of participants with familial hypobetalipoproteinemia (FBHL) who did not receive a study intervention. Data gathered for 15 weeks.

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.

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.

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

Baseline Apolipoprotein B
Samples were taken following an overnight fast.
Percent Change in Apolipoprotein B From Baseline to Day 99
Samples were taken following an overnight fast.
Baseline Low-Density Lipoprotein Cholesterol
Samples were taken following overnight fast.
Percent Change in Low-Density Lipoprotein Cholesterol From Baseline to Day 99
Samples were taken following an overnight fast.
Baseline Total Cholesterol
Samples were taken following an overnight fast.
Percent Change in Total Cholesterol From Baseline to Day 99
Samples were taken following an overnight fast.

Full Information

First Posted
August 7, 2006
Last Updated
September 9, 2016
Sponsor
Kastle Therapeutics, LLC
Collaborators
Ionis Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00362180
Brief Title
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

2. Study Status

Record Verification Date
September 2016
Overall Recruitment Status
Completed
Study Start Date
July 2006 (undefined)
Primary Completion Date
March 2010 (Actual)
Study Completion Date
September 2010 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Kastle Therapeutics, LLC
Collaborators
Ionis Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
38 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Cohort A: mipomersen
Arm Type
Experimental
Arm Description
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 Title
Cohort A: placebo
Arm Type
Placebo Comparator
Arm Description
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 Title
Cohort D: mipomersen
Arm Type
Experimental
Arm Description
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 Title
Cohort D: placebo
Arm Type
Placebo Comparator
Arm Description
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 Title
Cohort E: mipomersen
Arm Type
Experimental
Arm Description
Participants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly mipomersen 200 mg injections for 13 weeks.
Arm Title
Cohort E: placebo
Arm Type
Placebo Comparator
Arm Description
Participants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly placebo injections for 13 weeks.
Arm Title
Cohort F: no intervention
Arm Type
No Intervention
Arm Description
A reference group of participants with familial hypobetalipoproteinemia (FBHL) who did not receive a study intervention. Data gathered for 15 weeks.
Arm Title
Cohort G: mipomersen
Arm Type
Experimental
Arm Description
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 Title
Cohort G: placebo followed by mipomersen
Arm Type
Placebo Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
mipomersen
Other Intervention Name(s)
ISIS 301012, mipomersen sodium, Kynamro™
Intervention Description
200 mg subcutaneous injections
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
subcutaneous injections
Primary Outcome Measure Information:
Title
Change From Baseline in Liver Triglyceride (TG) Content As Measured by Magnetic Resonance Spectroscopy (MRS)
Description
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.
Time Frame
Baseline, Day 26, Day 99
Secondary Outcome Measure Information:
Title
Baseline Apolipoprotein B
Description
Samples were taken following an overnight fast.
Time Frame
Baseline
Title
Percent Change in Apolipoprotein B From Baseline to Day 99
Description
Samples were taken following an overnight fast.
Time Frame
Day 26 and Day 99
Title
Baseline Low-Density Lipoprotein Cholesterol
Description
Samples were taken following overnight fast.
Time Frame
Baseline
Title
Percent Change in Low-Density Lipoprotein Cholesterol From Baseline to Day 99
Description
Samples were taken following an overnight fast.
Time Frame
Day 26 and Day 99
Title
Baseline Total Cholesterol
Description
Samples were taken following an overnight fast.
Time Frame
Baseline
Title
Percent Change in Total Cholesterol From Baseline to Day 99
Description
Samples were taken following an overnight fast.
Time Frame
Day 26 and Day 99

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Genzyme, a Sanofi Company
Official's Role
Study Director
Facility Information:
City
Amsterdam
ZIP/Postal Code
1105 AZ
Country
Netherlands

12. IPD Sharing Statement

Citations:
PubMed Identifier
20008831
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.
Results Reference
result

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Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration

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