Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia

August 1, 2016 updated by: Kastle Therapeutics, LLC

An Open-Label Extension Study to Assess the Long-term Safety and Efficacy of Mipomersen in Subjects With Familial Hypercholesterolemia

The purpose of this study is to evaluate the safety and efficacy of extended dosing of mipomersen in patients with familial hypercholesterolemia on lipid-lowering therapy who have completed either the 301012-CS8 (NCT00280995) or 301012-CS9 (NCT00281008) clinical drug trials.

Study Overview

Detailed Description

Familial Hypercholesterolemia (FH) is an autosomal dominant metabolic disorder characterized by markedly elevated low density lipoprotein (LDL), premature onset of atherosclerosis, and development of xanthomata. There are two distinct subpopulations that have a high unmet medical need due to the lack of alternative therapy: homozygotes, who have two defective LDL receptor (LDL-R) genes, and heterozygotes with a history of cardiovascular disease (CVD) on maximally tolerated therapy. Treatment for FH is directed at lowering plasma levels of LDL-C.

Mipomersen is an antisense drug targeted to human apolipoprotein B (apoB), the principal apolipoprotein of atherogenic LDL-C and its metabolic precursor, very low density lipoprotein (VLDL). Mipomersen is complimentary to the coding region of the messenger ribonucleic acid (mRNA) for apo-B. Inhibition of apo-B would be expected to impair VLDL synthesis and result in lowered levels of LDL-C.

In early clinical trials, mipomersen has been shown to reduce levels of LDL-C to recommended target levels in some participants.

This was an open-label extension study, which consisted of a ≤2-week screening period, up to 3 years of treatment with mipomersen, and a 24-week post-treatment follow-up period. Patients who participated in Cohorts A, B, or C in study 301012-CS9 were randomized in a 1:1 ratio to mipomersen 200 mg once a week (QW) or 200 mg mipomersen every other week (QOW) for up to 3 years. Patients randomized to mipomersen 200 mg QOW were allowed to receive mipomersen 200 mg QW at the Investigator's discretion after the first 52 weeks of the treatment period. Patients who participated in study 301012-CS8 or Cohort D of study 301012-CS9 received 200 mg mipomersen QW for up to 3 years.

Study Type

Interventional

Enrollment (Actual)

21

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

    • Illinois
      • Chicago, Illinois, United States, 60654
    • Maine
      • Auburn, Maine, United States, 04210
      • Biddeford, Maine, United States, 04005
      • Scarborough, Maine, United States, 04074
    • Ohio
      • Cincinnati, Ohio, United States, 45212

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

12 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

- Satisfactory completion of dosing and Week 7 or Week 15 assessments (depending on the treatment and dose received) in their initial study (Protocol 301012-CS8 (NCT00280995) or 301012-CS9 (NCT00281008)).

Exclusion Criteria:

- Have a new condition or worsening of existing condition which in the opinion of the Investigator would make the patient unsuitable for enrollment, or could interfere with patient's participation in or completion of the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Mipomersen 200 mg per week
Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.
200 mg/ml, in 1 ml solution for subcutaneous injection.
Other Names:
  • ISIS 301012
  • Kynamro™
Experimental: Mipomersen 200 mg every other week
Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
200 mg/ml, in 1 ml solution for subcutaneous injection.
Other Names:
  • ISIS 301012
  • Kynamro™

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)
Time Frame: Baseline and Weeks 52 and 104
LDL cholesterol was measured in mg/dL. Samples were taken following an overnight fast. For patients with triglycerides <400 mg/dL, LDL-C was obtained using Friedewald's calculation; and for patients with triglycerides ≥400 mg/dL, LDL-C was directly measured by the central laboratory using ultracentrifugation. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104
Low-density Lipoprotein Cholesterol (LDL-C) Over Time
Time Frame: Baseline and Weeks 52 and 104.
Samples were taken following an overnight fast. For patients with triglycerides <400 mg/dL, LDL-C was obtained using Friedewald's calculation; and for patients with triglycerides ≥400 mg/dL, LDL-C was directly measured by the central laboratory using ultracentrifugation. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percent Change From Baseline in Apolipoprotein B
Time Frame: Baseline and Weeks 52 and 104
Apolipoprotein B was measured in mg/dL. Samples were taken following an overnight fast. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104
Apolipoprotein B Over Time
Time Frame: Baseline and Weeks 52 and 104.
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104.
Percent Change From Baseline in Total Cholesterol
Time Frame: Baseline and Weeks 52 and 104.
Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast.
Baseline and Weeks 52 and 104.
Total Cholesterol Over Time
Time Frame: Baseline and Weeks 52 and 104.
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104.
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol
Time Frame: Baseline and Weeks 52 and 104.
Non-high-density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast.
Baseline and Weeks 52 and 104.
Non-High-Density Lipoprotein Cholesterol Over Time
Time Frame: Baseline and Weeks 52 and 104.
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104.
Number of Participants With Treatment-Emergent Adverse Events (AEs)
Time Frame: 2 years
AEs were considered as related if assessed by the Investigator as possibly, probably or definitely related to study drug. The severity of each event was assessed using the following categories: Mild (symptom(s) barely noticeable to the patient or do not make the patient uncomfortable); Moderate (symptom(s) of a sufficient severity to make the patient uncomfortable, performance of daily activities is influenced) or Severe (symptom(s) of a sufficient severity to cause the patient severe discomfort, may cause cessation of treatment with the study drug). Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above.
2 years
Percent Change From Baseline in Clinical Chemistry Parameters
Time Frame: Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Percent Change From Baseline in Hematology Parameters
Time Frame: Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment
Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment
Percent Change From Baseline in Blood Pressure
Time Frame: Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Percent Change From Baseline in Pulse Rate
Time Frame: Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Percent Change From Baseline in Respiratory Rate
Time Frame: Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Percent Change From Baseline in Triglycerides
Time Frame: Baseline and Weeks 52 and 104.
Triglycerides were measured in mg/dL. Samples were taken following an overnight fast.
Baseline and Weeks 52 and 104.
Triglycerides Over Time
Time Frame: Baseline and Weeks 52 and 104.
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104.
Percent Change From Baseline in Lipoprotein(a)
Time Frame: Baseline and Weeks 52 and 104.
Lipoprotein(a) was measured in mg/dL. Samples were taken following an overnight fast.
Baseline and Weeks 52 and 104.
Lipoprotein(a) Over Time
Time Frame: Baseline and Weeks 52 and 104.
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104.
Percent Change From Baseline in Very-Low-Density Lipoprotein (VLDL) Cholesterol
Time Frame: Baseline and Weeks 52 and 104.
Very-Low-Density Lipoprotein (VLDL) Cholesterol was measured in mg/dL. Samples were taken following an overnight fast.
Baseline and Weeks 52 and 104.
Very-Low-Density Lipoprotein (VLDL) Cholesterol Over Time
Time Frame: Baseline and Weeks 52 and 104.
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104.
Percent Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol
Time Frame: Baseline and Weeks 52 and 104.
Baseline and Weeks 52 and 104.
Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol Over Time
Time Frame: Baseline and Weeks 52 and 104.
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104.
Percent Change From Baseline in Apolipoprotein A1
Time Frame: Baseline and Weeks 52 and 104.
Apolipoprotein A1 was measured in mg/dL. Samples were taken following an overnight fast.
Baseline and Weeks 52 and 104.
Apolipoprotein A1 Over Time
Time Frame: Baseline and Weeks 52 and 104.
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104.
Percent Change From Baseline in High-Density Lipoprotein Cholesterol
Time Frame: Baseline and Weeks 52 and 104.
High-Density Lipoprotein (HDL) Cholesterol was measured in mg/dL. Samples were taken following an overnight fast.
Baseline and Weeks 52 and 104.
High-Density Lipoprotein Cholesterol Over Time
Time Frame: Baseline and Weeks 52 and 104.
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Baseline and Weeks 52 and 104.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

May 1, 2007

Primary Completion (Actual)

March 1, 2011

Study Completion (Actual)

July 1, 2011

Study Registration Dates

First Submitted

May 22, 2007

First Submitted That Met QC Criteria

May 22, 2007

First Posted (Estimate)

May 24, 2007

Study Record Updates

Last Update Posted (Estimate)

September 9, 2016

Last Update Submitted That Met QC Criteria

August 1, 2016

Last Verified

August 1, 2016

More Information

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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