Safety and Efficacy of Mipomersen (ISIS 301012) As Add-on Therapy in High Risk Hypercholesterolemic Patients

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety and efficacy of dosing with mipomersen for 26 weeks in patients with high cholesterol who are on a maximally tolerated dose of statin and who have a diagnosis that puts them at least at high risk of coronary heart disease (CHD).

Detailed Description
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Hypercholesterolemia is characterized by markedly elevated low density lipoproteins (LDL). Elevated LDL is a major risk factor for 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 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 patients with high cholesterol who are at high risk for CHD and who are already on the maximally tolerated dose of statin. This study consisted of a 26-week treatment period and a 24-week post-treatment follow-up period. Participants who finished treatment or who discontinued prematurely from the study for any reason were assessed for safety for 24 weeks after the last study drug dose.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) as Add-on Therapy in High Risk Hypercholesterolemic Patients

Conditions
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Hypercholesterolemia, Coronary Heart Disease

Intervention / Treatment
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* Drug: Mipomersen sodium
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of hypercholesterolemia (LDL-C ≥ 100 mg/dL) At high risk of CHD On stable, maximally tolerated statin therapy 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, liver disease, cancer, type I diabetes.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants received placebo subcutaneous injection once a week for 26 weeks. | Drug: Placebo<br>* 1 mL matching placebo (i.e., vehicle consisting of 9 mg of sodium chloride, 0.004 mg of riboflavin, filled to 1 mL with water).<br>|
| Experimental: Mipomersen<br>Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks. | Drug: Mipomersen sodium<br>* 200 mg/mL<br>* Other names: Kynamro™;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the Primary Efficacy Time Point | LDL cholesterol was measured in mg/dL. Samples were taken following an overnight fast. LDL-C was obtained using Friedewald's calculation for patients with triglycerides ≤400 mg/dL and was directly measured by the central laboratory using ultracentrifugation for patients with triglycerides >400 mg/dL. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | 
| Low-density Lipoprotein Cholesterol (LDL-C) at Baseline and at the Primary Efficacy Time Point | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Apolipoprotein B at the Primary Efficacy Time Point | Apolipoprotein B was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | 
| Apolipoprotein B at Baseline and at the Primary Efficacy Time Point | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | 
| Percent Change From Baseline in Total Cholesterol at the Primary Efficacy Time Point | Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | 
| Total Cholesterol at Baseline and at the Primary Efficacy Time Point | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | 
| Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point | Non-high-density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment. | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). | 
| Non-High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point | The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment. | Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET; Week 28 or the post-baseline visit closest to 14 days after the last dose). |