Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia

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 extended dosing of mipomersen in patients with familial hypercholesterolemia on lipid-lowering therapy who have completed either the 301012-CS8 (NCT00280995) or 301012-CS9 (NCT00281008) clinical drug trials.

Detailed Description
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Familial Hypercholesterolemia (FH) is an autosomal dominant metabolic disorder characterized by markedly elevated low density lipoprotein (LDL), premature onset of atherosclerosis, and development of xanthomata. There are two distinct subpopulations that have a high unmet medical need due to the lack of alternative therapy: homozygotes, who have two defective LDL receptor (LDL-R) genes, and heterozygotes with a history of cardiovascular disease (CVD) on maximally tolerated therapy. Treatment for FH is directed at lowering plasma levels of LDL-C. Mipomersen is an antisense drug targeted to human apolipoprotein B (apoB), the principal apolipoprotein of atherogenic LDL-C and its metabolic precursor, very low density lipoprotein (VLDL). Mipomersen is complimentary to the coding region of the messenger ribonucleic acid (mRNA) for apo-B. Inhibition of apo-B would be expected to impair VLDL synthesis and result in lowered levels of LDL-C. In early clinical trials, mipomersen has been shown to reduce levels of LDL-C to recommended target levels in some participants. This was an open-label extension study, which consisted of a ≤2-week screening period, up to 3 years of treatment with mipomersen, and a 24-week post-treatment follow-up period. Patients who participated in Cohorts A, B, or C in study 301012-CS9 were randomized in a 1:1 ratio to mipomersen 200 mg once a week (QW) or 200 mg mipomersen every other week (QOW) for up to 3 years. Patients randomized to mipomersen 200 mg QOW were allowed to receive mipomersen 200 mg QW at the Investigator's discretion after the first 52 weeks of the treatment period. Patients who participated in study 301012-CS8 or Cohort D of study 301012-CS9 received 200 mg mipomersen QW for up to 3 years.

Official Title
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An Open-Label Extension Study to Assess the Long-term Safety and Efficacy of Mipomersen in Subjects With Familial Hypercholesterolemia

Conditions
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Lipid Metabolism, Inborn Errors, Hypercholesterolemia, Autosomal Dominant, Hyperlipidemias, Metabolic Diseases, Hyperlipoproteinemia Type II, Metabolism, Inborn Errors, Genetic Diseases, Inborn, Infant, Newborn, Diseases, Metabolic Disorder, Congenital Abnormalities, Hypercholesterolemia, Hyperlipoproteinemias, Dyslipidemias, Lipid Metabolism Disorders

Intervention / Treatment
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* Drug: mipomersen sodium


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Satisfactory completion of dosing and Week 7 or Week 15 assessments (depending on the treatment and dose received) in their initial study (Protocol 301012-CS8 (NCT00280995) or 301012-CS9 (NCT00281008)). Exclusion Criteria: - Have a new condition or worsening of existing condition which in the opinion of the Investigator would make the patient unsuitable for enrollment, or could interfere with patient's participation in or completion of the study.

Ages Eligible for Study
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Minimum Age: 12 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mipomersen 200 mg per week<br>Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years. | Drug: mipomersen sodium<br>* 200 mg/ml, in 1 ml solution for subcutaneous injection.<br>* Other names: Kynamro™;|
| Experimental: Mipomersen 200 mg every other week<br>Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period. | Drug: mipomersen sodium<br>* 200 mg/ml, in 1 ml solution for subcutaneous injection.<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) | LDL cholesterol 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. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study. | Baseline and Weeks 52 and 104 | 
| Low-density Lipoprotein Cholesterol (LDL-C) Over Time | 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. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study. | Baseline and Weeks 52 and 104. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Apolipoprotein B | Apolipoprotein B was measured in mg/dL. Samples were taken following an overnight fast. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study. | Baseline and Weeks 52 and 104 | 
| Apolipoprotein B Over Time | For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study. | Baseline and Weeks 52 and 104. | 
| Percent Change From Baseline in Total Cholesterol | Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. | Baseline and Weeks 52 and 104. | 
| Total Cholesterol Over Time | For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study. | Baseline and Weeks 52 and 104. | 
| Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol | Non-high-density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast. | Baseline and Weeks 52 and 104. | 
| Non-High-Density Lipoprotein Cholesterol Over Time | For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study. | Baseline and Weeks 52 and 104. | 
| Number of Participants With Treatment-Emergent Adverse Events (AEs) | AEs were considered as related if assessed by the Investigator as possibly, probably or definitely related to study drug. The severity of each event was assessed using the following categories: Mild (symptom(s) barely noticeable to the patient or do not make the patient uncomfortable); Moderate (symptom(s) of a sufficient severity to make the patient uncomfortable, performance of daily activities is influenced) or Severe (symptom(s) of a sufficient severity to cause the patient severe discomfort, may cause cessation of treatment with the study drug). Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention to prevent one of the outcomes listed above. | 2 years | 
| Percent Change From Baseline in Clinical Chemistry Parameters |  | Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment. | 
| Percent Change From Baseline in Hematology Parameters |  | Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment | 
| Percent Change From Baseline in Blood Pressure |  | Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment. | 
| Percent Change From Baseline in Pulse Rate |  | Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment. | 
| Percent Change From Baseline in Respiratory Rate |  | Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Familial Hypercholesterolemia, Heterozygous Familial Hypercholesterolemia, Homozygous Familial Hypercholesterolemia, ISIS 301012, mipomersen, Open Label Extension