- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT00362180
Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration
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 Overview
Status
Conditions
- Metabolic Diseases
- Congenital Abnormalities
- Infant, Newborn, Diseases
- Genetic Diseases, Inborn
- Dyslipidemias
- Metabolism, Inborn Errors
- Lipid Metabolism Disorders
- Hypercholesterolemia
- Hyperlipidemias
- Lipid Metabolism, Inborn Errors
- Hypobetalipoproteinemias
- Hypolipoproteinemias
- Hypolipoproteinemia
- Metabolic Disorder
Intervention / Treatment
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.
Study Type
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
-
Amsterdam, Netherlands, 1105 AZ
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Quadruple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
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.
|
200 mg subcutaneous injections
Other Names:
|
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.
|
subcutaneous injections
|
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.
|
200 mg subcutaneous injections
Other Names:
|
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.
|
subcutaneous injections
|
Experimental: Cohort E: mipomersen
Participants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly mipomersen 200 mg injections for 13 weeks.
|
200 mg subcutaneous injections
Other Names:
|
Placebo Comparator: Cohort E: placebo
Participants with uncomplicated heterozygous familial hypercholesterolemia (HeFH) treated with weekly placebo injections for 13 weeks.
|
subcutaneous injections
|
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.
|
200 mg subcutaneous injections
Other Names:
|
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.
|
200 mg subcutaneous injections
Other Names:
subcutaneous injections
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Change From Baseline in Liver Triglyceride (TG) Content As Measured by Magnetic Resonance Spectroscopy (MRS)
Time Frame: Baseline, Day 26, Day 99
|
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
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Baseline Apolipoprotein B
Time Frame: Baseline
|
Samples were taken following an overnight fast.
|
Baseline
|
Percent Change in Apolipoprotein B From Baseline to Day 99
Time Frame: Day 26 and Day 99
|
Samples were taken following an overnight fast.
|
Day 26 and Day 99
|
Baseline Low-Density Lipoprotein Cholesterol
Time Frame: Baseline
|
Samples were taken following overnight fast.
|
Baseline
|
Percent Change in Low-Density Lipoprotein Cholesterol From Baseline to Day 99
Time Frame: Day 26 and Day 99
|
Samples were taken following an overnight fast.
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Day 26 and Day 99
|
Baseline Total Cholesterol
Time Frame: Baseline
|
Samples were taken following an overnight fast.
|
Baseline
|
Percent Change in Total Cholesterol From Baseline to Day 99
Time Frame: Day 26 and Day 99
|
Samples were taken following an overnight fast.
|
Day 26 and Day 99
|
Collaborators and Investigators
Sponsor
Collaborators
Publications and helpful links
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Disease
- Dyslipidemias
- Congenital Abnormalities
- Hypercholesterolemia
- Hyperlipidemias
- Metabolism, Inborn Errors
- Metabolic Diseases
- Lipid Metabolism Disorders
- Genetic Diseases, Inborn
- Infant, Newborn, Diseases
- Hyperlipoproteinemias
- Hypobetalipoproteinemias
- Lipid Metabolism, Inborn Errors
- Hypolipoproteinemias
- Molecular Mechanisms of Pharmacological Action
- Antimetabolites
- Anticholesteremic Agents
- Hypolipidemic Agents
- Lipid Regulating Agents
- Mipomersen
Other Study ID Numbers
- 301012-CS10
- 2005-005783-90 (EudraCT Number)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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