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

This study has been completed.
Sponsor:
Collaborator:
Isis Pharmaceuticals
Information provided by (Responsible Party):
Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier:
NCT00477594
First received: May 22, 2007
Last updated: December 2, 2013
Last verified: December 2013
  Purpose

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.


Condition Intervention Phase
Lipid Metabolism, Inborn Errors
Hypercholesterolemia, Autosomal Dominant
Hyperlipidemias
Metabolic Diseases
Hyperlipoproteinemia Type II
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Infant, Newborn, Diseases
Metabolic Disorder
Congenital Abnormalities
Hypercholesterolemia
Hyperlipoproteinemias
Dyslipidemias
Lipid Metabolism Disorders
Drug: mipomersen sodium
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label Extension Study to Assess the Long-term Safety and Efficacy of Mipomersen in Subjects With Familial Hypercholesterolemia

Resource links provided by NLM:


Further study details as provided by Sanofi:

Primary Outcome Measures:
  • Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline and Weeks 52 and 104 ] [ Designated as safety issue: No ]
    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.

  • Low-density Lipoprotein Cholesterol (LDL-C) Over Time [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Percent Change From Baseline in Apolipoprotein B [ Time Frame: Baseline and Weeks 52 and 104 ] [ Designated as safety issue: No ]
    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.

  • Apolipoprotein B Over Time [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Total Cholesterol [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast.

  • Total Cholesterol Over Time [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    Non-high-density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast.

  • Non-High-Density Lipoprotein Cholesterol Over Time [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    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.

  • Number of Participants With Treatment-Emergent Adverse Events (AEs) [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
    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.

  • 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. ] [ Designated as safety issue: Yes ]
  • 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 ] [ Designated as safety issue: Yes ]
  • 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. ] [ Designated as safety issue: Yes ]
  • 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. ] [ Designated as safety issue: Yes ]
  • 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. ] [ Designated as safety issue: Yes ]

Other Outcome Measures:
  • Percent Change From Baseline in Triglycerides [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    Triglycerides were measured in mg/dL. Samples were taken following an overnight fast.

  • Triglycerides Over Time [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Lipoprotein(a) [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    Lipoprotein(a) was measured in mg/dL. Samples were taken following an overnight fast.

  • Lipoprotein(a) Over Time [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Very-Low-Density Lipoprotein (VLDL) Cholesterol [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    Very-Low-Density Lipoprotein (VLDL) Cholesterol was measured in mg/dL. Samples were taken following an overnight fast.

  • Very-Low-Density Lipoprotein (VLDL) Cholesterol Over Time [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
  • Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol Over Time [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in Apolipoprotein A1 [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    Apolipoprotein A1 was measured in mg/dL. Samples were taken following an overnight fast.

  • Apolipoprotein A1 Over Time [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    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.

  • Percent Change From Baseline in High-Density Lipoprotein Cholesterol [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    High-Density Lipoprotein (HDL) Cholesterol was measured in mg/dL. Samples were taken following an overnight fast.

  • High-Density Lipoprotein Cholesterol Over Time [ Time Frame: Baseline and Weeks 52 and 104. ] [ Designated as safety issue: No ]
    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.


Enrollment: 21
Study Start Date: May 2007
Study Completion Date: July 2011
Primary Completion Date: March 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Mipomersen 200 mg per week
Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.
Drug: mipomersen sodium
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.
Drug: mipomersen sodium
200 mg/ml, in 1 ml solution for subcutaneous injection.
Other Names:
  • ISIS 301012
  • Kynamro™

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.

  Eligibility

Ages Eligible for Study:   12 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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.

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00477594

Locations
United States, Illinois
Chicago, Illinois, United States, 60654
United States, Maine
Auburn, Maine, United States, 04210
Biddeford, Maine, United States, 04005
Scarborough, Maine, United States, 04074
United States, Ohio
Cincinnati, Ohio, United States, 45212
Sponsors and Collaborators
Genzyme, a Sanofi Company
Isis Pharmaceuticals
Investigators
Study Director: Medical Monitor Genzyme, a Sanofi Company
  More Information

No publications provided by Sanofi

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Sanofi ( Genzyme, a Sanofi Company )
ClinicalTrials.gov Identifier: NCT00477594     History of Changes
Other Study ID Numbers: 301012-CS17, 2007-001024-12
Study First Received: May 22, 2007
Results First Received: February 25, 2013
Last Updated: December 2, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Sanofi:
Familial Hypercholesterolemia
Heterozygous Familial Hypercholesterolemia
Homozygous Familial Hypercholesterolemia
ISIS 301012
mipomersen
Open Label Extension

Additional relevant MeSH terms:
Congenital Abnormalities
Genetic Diseases, Inborn
Hypercholesterolemia
Hyperlipoproteinemia Type II
Hyperlipidemias
Hyperlipoproteinemias
Infant, Newborn, Diseases
Lipid Metabolism, Inborn Errors
Metabolic Diseases
Metabolism, Inborn Errors
Lipid Metabolism Disorders
Sphingolipidoses
Dyslipidemias
Lysosomal Storage Diseases, Nervous System
Brain Diseases, Metabolic, Inborn
Brain Diseases, Metabolic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Lipidoses
Lysosomal Storage Diseases

ClinicalTrials.gov processed this record on July 28, 2014