Clinical Trial: Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

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 o

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 Summary:

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 w
Sponsor: Kastle Therapeutics, LLC

Current Primary Outcome: 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.


Original Primary Outcome:

  • Change in liver triglyceride content from Baseline
  • All AEs and SAEs
  • Laboratory results
  • Vital signs and ECG
  • Percent reduction in total cholesterol, LDL-C, and apoB from Baseline


Current Secondary Outcome:

  • Baseline Apolipoprotein B [ Time Frame: Baseline ]
    Samples were taken following an overnight fast.
  • Percent Change in Apolipoprotein B From Baseline to Day 99 [ Time Frame: Day 26 and Day 99 ]
    Samples were taken following an overnight fast.
  • Baseline Low-Density Lipoprotein Cholesterol [ Time Frame: Baseline ]
    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 ]
    Samples were taken following an overnight fast.
  • Baseline Total Cholesterol [ Time Frame: Baseline ]
    Samples were taken following an overnight fast.
  • Percent Change in Total Cholesterol From Baseline to Day 99 [ Time Frame: Day 26 and Day 99 ]
    Samples were taken following an overnight fast.


Original Secondary Outcome:

Information By: Kastle Therapeutics, LLC

Dates:
Date Received: August 7, 2006
Date Started: July 2006
Date Completion:
Last Updated: September 9, 2016
Last Verified: September 2016