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

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:

MedlinePlus related topics: Cholesterol Coronary Artery Disease Heart Diseases

Drug Information available for: Mipomersen sodium Mipomersen

U.S. FDA Resources

Further study details as provided by Genzyme:

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00794664

Show 27 Study Locations

Sponsors and Collaborators

Genzyme

Isis Pharmaceuticals

Investigators

Study Director:

Medical Monitor

Genzyme

More Information

No publications provided by Genzyme

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

McGowan MP, Tardif JC, Ceska R, Burgess LJ, Soran H, Gouni-Berthold I, Wagener G, Chasan-Taber S. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7(11):e49006. doi: 10.1371/journal.pone.0049006. Epub 2012 Nov 13.

Responsible Party:	Genzyme
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
Myocardial Ischemia
Coronary Disease
Heart Diseases
Hypercholesterolemia
Cardiovascular Diseases
Arteriosclerosis

Arterial Occlusive Diseases
Vascular Diseases
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases

ClinicalTrials.gov processed this record on June 18, 2013