Safety and Efficacy of Mipomersen in Patients With Severe Hypercholesterolemia on a Maximally Tolerated Lipid-Lowering Regimen and Who Are Not on Apheresis

This study has been completed.
Sponsor:
Collaborator:
Isis Pharmaceuticals
Information provided by (Responsible Party):
Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier:
NCT00794664
First received: November 19, 2008
Last updated: May 30, 2013
Last verified: May 2013
  Purpose

The purpose of the study is to evaluate the safety and efficacy of dosing with mipomersen for 26 weeks in treating severely hypercholesterolemic patients who are on a maximally tolerated lipid-lowering regimen and who are not on apheresis.


Condition Intervention Phase
Hypercholesterolemia
Coronary Heart Disease
Drug: Mipomersen
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Prospective Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Mipomersen in Patients With Severe Hypercholesterolemia on a Maximally Tolerated Lipid-Lowering Regimen and Who Are Not on Apheresis

Resource links provided by NLM:


Further study details as provided by Genzyme, a Sanofi Company:

Primary Outcome Measures:
  • Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    LDL-C 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. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • LDL-C at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.


Secondary Outcome Measures:
  • Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    Apo-B was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Apo-B at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    Non-HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.


Other Outcome Measures:
  • Percentage Change From Baseline in Triglycerides at Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    Triglycerides were measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Triglycerides at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Percentage Change From Baseline in Lipoprotein(a) at Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    Lipoprotein(a) was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Percentage Change From Baseline in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) at Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    VLDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • VLDL-C at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol (LDL-C) to High-density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    LDL-C and HDL-C were measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Percent Change From Baseline in Apolipoprotein A1 (Apo-A1) at Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    Apo-A1 was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Apo-A1 at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • Percentage Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  • HDL-C at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ] [ Designated as safety issue: No ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.


Enrollment: 58
Study Start Date: January 2009
Study Completion Date: October 2010
Primary Completion Date: May 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
Weekly subcutaneous injections for 26 weeks
Drug: Placebo
1 mL weekly subcutaneous injections for 26 weeks
Other Name: placebo
Experimental: Mipomersen
200 mg weekly subcutaneous injections for 26 weeks
Drug: Mipomersen
200 mg (1 mL), weekly subcutaneous injections for 26 weeks
Other Names:
  • ISIS 301012
  • Mipomersen sodium
  • Kynamro™

Detailed Description:

Hypercholesterolemia is characterized by markedly elevated low density lipoproteins (LDL). Elevated LDL is a major risk factor for coronary heart disease (CHD).

Mipomersen is an antisense drug that reduces a protein in the liver cells called apolipoprotein B (Apo-B). Apo-B plays a role in producing low density lipoprotein cholesterol (LDL-C) (the "bad" cholesterol) and moving it from the liver to one's bloodstream. High LDL-C is an independent risk factor for the development of coronary heart disease (CHD) or other diseases of blood vessels. It has been shown that lowering LDL-C reduces the risk of heart attacks and other major adverse cardiovascular events. The purpose of this study is to determine whether mipomersen safely and effectively lowers LDL-C in severely hypercholesterolemic patients who are on a maximally tolerated lipid-lowering regimen and who are not on apheresis.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Fasting LDL-C ≥200 mg/dL (5.1 mmol/L) at screening and the presence of at least 1 of the following criteria:

    • Myocardial infarction (MI)
    • Percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)
    • Coronary artery disease documented by angiography or any other accepted imaging technique
    • Positive exercise test (≥1 mm ST-depression at maximal exercise or test terminated because of angina) or a perfusion defect (e.g., thallium or single photon emission computed tomography)
    • Other clinical atherosclerotic diseases: peripheral artery disease, symptomatic carotid artery disease, abdominal aortic aneurysm
    • Or, if alternative above were not met, fasting LDL-C ≥300 mg/dL (7.8 mmol/L)
  • On stable, maximally tolerated statin therapy for 8 weeks
  • On stable, medication from an additional class of hypolipidemic agents for 8 weeks.
  • On stable, low fat diet for 12 weeks
  • Stable weight for 6 weeks

Exclusion Criteria:

  • Significant health problems in the recent past including heart attack, stroke, coronary syndrome, unstable angina, heart failure, significant arrhythmia, hypertension, blood disorders, liver disease, cancer, digestive disorders, Type I diabetes, or uncontrolled Type II diabetes
  • Apheresis within 3 months prior to Screening or expected to start apheresis during the treatment phase
  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: NCT00794664

  Show 27 Study Locations
Sponsors and Collaborators
Genzyme, a Sanofi Company
Isis Pharmaceuticals
Investigators
Study Director: Medical Monitor Genzyme, a Sanofi Company
  More Information

No publications provided by Genzyme, a Sanofi Company

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier: NCT00794664     History of Changes
Other Study ID Numbers: MIPO3500108, 2008-006020-53
Study First Received: November 19, 2008
Results First Received: February 15, 2013
Last Updated: May 30, 2013
Health Authority: United States: Food and Drug Administration
Canada: Health Canada
South Africa: Medicines Control Council
Czech Republic: State Institute for Drug Control
Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Coronary Artery Disease
Coronary Disease
Heart Diseases
Hypercholesterolemia
Myocardial Ischemia
Arterial Occlusive Diseases
Arteriosclerosis
Cardiovascular Diseases
Dyslipidemias
Hyperlipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Vascular Diseases
Mipomersen
Anticholesteremic Agents
Antimetabolites
Diagnostic Uses of Chemicals
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Molecular Probes
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 20, 2014