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

Phase 3

Completed

• Conditions: Heterozygous Familial; Hypercholesterolemia
• Interventions: Drug: mipomersen sodium 200 mg; Drug: Placebo; Drug: mipomersen sodium 70 mg

• Registration Number: NCT01475825
• Lead Sponsor: Kastle Therapeutics, LLC

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2011-11-17
• Study First Submitted QC: 2011-11-17
• Study First Posted: 2011-11-21
• Study Start: 2011-12
• Primary Completion: 2015-12-29
• Study Completion: 2015-12-29
• Results First Submitted: 2018-11-13
• Results First Submitted QC: 2019-02-26
• Status Verified: 2019-03
• Last Update Submitted: 2019-03-13
• Results First Posted: 2019-03-14
• Last Update Posted: 2019-03-26

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 309

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Regimen A: Mipomersen	mipomersen sodium 200 mg	Subcutaneous injection of mipomersen 200 mg once weekly
Regimen A: Placebo	Placebo	Placebo matching subcutaneous injection once weekly.
Regimen B: Mipomersen	mipomersen sodium 70 mg	Subcutaneous injection of mipomersen 70 mg thrice weekly.
Regimen B: Placebo	Placebo	Placebo matching subcutaneous injection thrice weekly.

Primary Outcome Measures

Name	Time	Method
Percent Change From Baseline To Primary Endpoint Visit (PET) In LDL-C In Cohort 1	Baseline and Week 61	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.

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 1	Baseline and Week 61	The percent change from baseline to PET in Lipoprotein A1 was measured in participants in Cohort 1 with HeFH during the Blinded Treatment Period.
Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 2	Baseline and Week 61	The percent change from baseline to PET in Lipoprotein A1 was measured in participants in Cohort 2 with HeFH during the Blinded Treatment Period.
Percent Change From Baseline To PET In LDL-C In Cohort 2	Baseline, PET (up to 60 weeks)	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.
Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 1	Baseline and Week 61	The percent change from baseline to PET in Apo B was measured in participants in Cohort 1 with HeFH during the Blinded Treatment Period.
Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 2	Baseline and Week 61	The percent change from baseline to PET in Apo B was measured in participants in Cohort 2 with HeFH during the Blinded Treatment Period.