A Study of the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients With Familial Hypercholesterolemia and Inadequately Controlled Low-Density Lipoprotein Cholesterol

Study Overview
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Brief Summary
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Primary objective: Determine whether mipomersen (ISIS 301012) significantly reduces atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (severe HeFH), defined as low-density lipoprotein cholesterol (LDL-C) levels ≥200 mg/dL plus the presence of coronary heart disease (CHD)/risk equivalents or LDL-C levels ≥300 mg/dL regardless of the presence of CHD/risk equivalents (referred to as Cohort 1) compared to placebo. Two different mipomersen dosing regimens will be studied: subcutaneous (SC) mipomersen 200 mg once weekly versus placebo, and SC mipomersen 70 mg thrice weekly versus placebo. Secondary Objectives: Determine whether there are qualitative differences between the safety profiles of the 2 dosing regimens and placebo in Cohort 1, patients with HeFH with LDL-C levels ≥160 mg/dL and <200 mg/dL plus the presence of CHD/risk equivalents (referred to as Cohort 2), and the overall study population Determine whether there are qualitative differences between the tolerability of the 2 dosing regimens and placebo in Cohort 1, Cohort 2, and the overall study population Further characterize the pharmacokinetics (PK) of the 2 dosing regimens in Cohort 1, Cohort 2, and the overall study population Determine whether the 2 mipomersen dosing regimens significantly reduce atherogenic lipid levels in Cohort 2 compared to placebo Obtain additional data regarding ongoing safety and efficacy of mipomersen in patients with FH and inadequately controlled LDL-C who complete the primary efficacy assessment visit (PET) in the Blinded Treatment Period and continue treatment in Open-Label Continuation Period

Detailed Description
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The study consisted of a Screening period of up to 4 weeks, Blinded Treatment Phase of 60 weeks, Open-Label Continuation Period of 26 weeks, and Post-Treatment Phase of 24 weeks. Study Design, masking - Study treatment was blinded (double-blinded) through the Primary Efficacy Assessment Visit in the Blinded Treatment Period. Study treatment was open-label in the Open-Label Continuation Period.

Official Title
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A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Followed by an Open-Label Continuation Period to Assess the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients With Familial Hypercholesterolemia and Inadequately Controlled Low-Density Lipoprotein Cholesterol

Conditions
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Hypercholesterolemia, Heterozygous Familial

Intervention / Treatment
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* Drug: mipomersen sodium 200 mg
* Drug: Placebo
* Drug: mipomersen sodium 70 mg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of severe hypercholesterolemia (LDL-C ≥300 mg/dL (7.77 mmol/L) or LDL-C ≥200 mg/dL (5.18 mmol/L) with documented coronary heart disease (CHD) or CHD risk equivalents, or diagnosis of Heterozygous Familial Hypercholesterolemia and LDL-C ≥160 mg/dL (4.14 mmol/L) and <200 mg/dL (5.18 mmol/L)) On stable, maximally tolerated, statin therapy for at least 12 weeks or if statin intolerant, on at least 1 medication from another class of hypolipidemic agents (i.e., bile acid sequestrants, niacin/nicotinic acid, cholesterol absorption inhibitors, fibrates). On stable, low fat diet for 12 weeks Body mass index (BMI) ≤40 kg/m2 and 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

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 |
| --- | --- |
| Experimental: Regimen A: Mipomersen<br>Subcutaneous injection of mipomersen 200 mg once weekly | Drug: mipomersen sodium 200 mg<br>* Subcutaneous mipomersen 200 mg once weekly<br>* Other names: Kynamro (ISIS 301012);|
| Placebo Comparator: Regimen A: Placebo<br>Placebo matching subcutaneous injection once weekly. | Drug: Placebo<br>* Placebo vehicle for subcutaneous injection.<br>|
| Experimental: Regimen B: Mipomersen<br>Subcutaneous injection of mipomersen 70 mg thrice weekly. | Drug: mipomersen sodium 70 mg<br>* Subcutaneous mipomersen 70 mg thrice weekly<br>* Other names: Kynamro (ISIS 301012);|
| Placebo Comparator: Regimen B: Placebo<br>Placebo matching subcutaneous injection thrice weekly. | Drug: Placebo<br>* Placebo vehicle for subcutaneous injection.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline To Primary Endpoint Visit (PET) In LDL-C In Cohort 1 | The percent change from baseline to PET in LDL-C was measured in Cohort 1, which included participants with severe heterozygous familial hypercholesterolemia (HeFH). Severe HeFH was defined as LDL-C levels ≥200 mg/deciliter (dL) plus the presence of coronary heart disease (CHD)/risk equivalents or LDL-C levels ≥300 mg/dL regardless of the presence of CHD/risk equivalents. | Baseline and Week 61 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline To PET In LDL-C In Cohort 2 | The percent change from baseline to PET in LDL-C was measured in Cohort 2, which included participants with HeFH with LDL-C levels ≥160 mg/dL and <200 mg/dL, plus the presence of CHD/risk equivalents. | Baseline, PET (up to 60 weeks) | 
| Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 1 | The percent change from baseline to PET in Apo B was measured in participants in Cohort 1 with HeFH during the Blinded Treatment Period. | Baseline and Week 61 | 
| Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 2 | The percent change from baseline to PET in Apo B was measured in participants in Cohort 2 with HeFH during the Blinded Treatment Period. | Baseline and Week 61 | 
| Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 1 | The percent change from baseline to PET in Lipoprotein A1 was measured in participants in Cohort 1 with HeFH during the Blinded Treatment Period. | Baseline and Week 61 | 
| Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 2 | The percent change from baseline to PET in Lipoprotein A1 was measured in participants in Cohort 2 with HeFH during the Blinded Treatment Period. | Baseline and Week 61 |