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

Phase 3

Completed

• Conditions: Hypercholesterolemia; Coronary Heart Disease
• Interventions: Drug: Placebo; Drug: Mipomersen

• Registration Number: NCT00794664
• Lead Sponsor: Kastle Therapeutics, LLC

Brief Summary

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.

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.

Study Timeline

• Study First Submitted: 2008-11-19
• Study First Submitted QC: 2008-11-19
• Study First Posted: 2008-11-20
• Study Start: 2009-01
• Primary Completion: 2010-05
• Study Completion: 2010-10
• Disposition First Submitted: 2010-10-02
• Disposition First Submitted QC: 2010-10-02
• Disposition First Posted: 2010-10-05
• Results First Submitted: 2013-02-15
• Results First Submitted QC: 2013-02-15
• Results First Posted: 2013-03-21
• Status Verified: 2016-08
• Last Update Submitted: 2016-08-01
• Last Update Posted: 2016-09-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 58

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Weekly subcutaneous injections for 26 weeks
Mipomersen	Mipomersen	200 mg weekly subcutaneous injections for 26 weeks

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	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)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	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

Name	Time	Method
Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	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.
Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	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)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	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.
Apo-B at Baseline and the Primary Efficacy Time Point (PET)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	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)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	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)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	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.