Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration

NCT00362180 | Completed Phase 2 Results DMC

• 2 other identifiers: 301012-CS102005-005783-90
• Study Type: interventional
• Target: 38
• Locations: 1 country
• Sites: 1

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.

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

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (6)

• Baseline Apolipoprotein B

  Baseline

• Percent Change in Apolipoprotein B From Baseline to Day 99

  Day 26 and Day 99

• Baseline Low-Density Lipoprotein Cholesterol

  Baseline

• Percent Change in Low-Density Lipoprotein Cholesterol From Baseline to Day 99

  Day 26 and Day 99

• Baseline Total Cholesterol

  Baseline

Study Arms (9)

Cohort A: mipomersen

EXPERIMENTAL

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

Cohort A: placebo

PLACEBO COMPARATOR

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

Cohort D: mipomersen

EXPERIMENTAL

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

Cohort D: placebo

PLACEBO COMPARATOR

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

Cohort E: mipomersen

EXPERIMENTAL

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

Drug: mipomersen

Cohort E: placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Cohort F: no intervention

NO INTERVENTION

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

Cohort G: mipomersen

EXPERIMENTAL

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

Cohort G: placebo followed by mipomersen

PLACEBO COMPARATOR

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; Drug: Placebo

Interventions

mipomersen DRUG

200 mg subcutaneous injections

Also known as: ISIS 301012, mipomersen sodium, Kynamro™

Cohort A: mipomersen; Cohort D: mipomersen; Cohort E: mipomersen; Cohort G: mipomersen; Cohort G: placebo followed by mipomersen

Placebo DRUG

subcutaneous injections

Cohort A: placebo; Cohort D: placebo; Cohort E: placebo; Cohort G: placebo followed by mipomersen

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Kastle Therapeutics, LLC: lead
• Ionis Pharmaceuticals, Inc.: collaborator

Study Sites (1)

Unknown Facility

Amsterdam, 1105 AZ, Netherlands

Location

Related 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: 10.1194/jlr.M002915. Epub 2009 Dec 14.

  PMID: 20008831 RESULT

MeSH Terms

Conditions

Lipid Metabolism, Inborn Errors; Hyperlipidemias; Metabolic Diseases; Hypolipoproteinemias; Hypobetalipoproteinemias; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Congenital Abnormalities; Hypercholesterolemia; Dyslipidemias; Lipid Metabolism Disorders

Interventions

mipomersen

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases

Limitations and Caveats

The limitations to this study are 1) post-hoc amendments that caused early termination of cohorts and limited the accomplishment of study objectives and 2) post-hoc amendments which added cohorts into the study that were not previously specified.

Results Point of Contact

• Title: Christopher Bryant, Ph.D.
• Organization: Kastle Therapeutics, LLC

cbryant@kastletx.com

8152633913

Study Officials

• Medical Monitor

  Genzyme, a Sanofi Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 7, 2006
• First Posted: August 9, 2006
• Study Start: July 1, 2006
• Primary Completion: March 1, 2010
• Study Completion: September 1, 2010
• Last Updated: October 21, 2016
• Results First Posted: June 24, 2015

Record last verified: 2016-09

Locations

NL (1)