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 (FOCUS FH)

Study Description

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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

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia; Heterozygous Familial	Drug: mipomersen sodium 200 mg; Drug: Placebo; Drug: mipomersen sodium 70 mg	Phase 3

Detailed Description:

The study consists 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 is blinded (double-blinded) through the Primary Efficacy Assessment Visit in the Blinded Treatment Period. Study treatment is open-label in the Open-Label Continuation Period.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	310 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	December 2011
Actual Primary Completion Date :	February 2016
Actual Study Completion Date :	February 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Blinded mipomersen 200 mg once weekly; Mipomersen sodium 200 mg (1 mL), subcutaneous injections administered once every other week for the first 8 weeks followed by once every week for 52 weeks.	Drug: mipomersen sodium 200 mg; 200 mg (200 mg/mL in a volume of 1 mL), subcutaneous injections; Other Name: Kynamro (ISIS 301012)
Placebo Comparator: Placebo once weekly; Placebo subcutaneous injection (1 mL) administered once every other week for the first 8 weeks followed by once a week for 52 weeks.	Drug: Placebo; Placebo vehicle for subcutaneous injection.
Experimental: Blinded mipomersen 70 mg thrice weekly; Mipomersen sodium 70 mg (0.5 mL), subcutaneous injections administered three times a week every other week for the first 8 weeks followed by three times a week every week for 52 weeks.	Drug: mipomersen sodium 70 mg; 70 mg (140 mg/mL in a volume of 0.5 mL), subcutaneous injections; Other Name: Kynamro (ISIS 301012)
Placebo Comparator: Placebo thrice weekly; Placebo subcutaneous injection (0.5 mL) three times a week every other week for the first 8 weeks followed by three times every week for 52 weeks.	Drug: Placebo; Placebo vehicle for subcutaneous injection.
Experimental: Open-label mipomersen 200 mg once weekly; Mipomersen sodium 200 mg (1 mL), subcutaneous injections administered once every week for 26 weeks following completion of blinded treatment period	Drug: mipomersen sodium 200 mg; 200 mg (200 mg/mL in a volume of 1 mL), subcutaneous injections; Other Name: Kynamro (ISIS 301012)
Experimental: Open-label mipomersen 70 mg thrice weekly; Mipomersen sodium 70 mg (0.5 mL), subcutaneous injections administered three times a week for 26 weeks following completion of blinded treatment period.	Drug: mipomersen sodium 70 mg; 70 mg (140 mg/mL in a volume of 0.5 mL), subcutaneous injections; Other Name: Kynamro (ISIS 301012)

Outcome Measures

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Primary Outcome Measures :

1. Percent change from Baseline in low-density lipoprotein cholesterol (LDL-C) in Cohort 1 [ Time Frame: Baseline to primary endpoint visit (PET) ]

Secondary Outcome Measures :

1. Percent Change from Baseline in Apolipoprotein B (Apo B) [ Time Frame: Baseline to PET ]
2. Percent Change from Baseline in Lipoprotein a [ Time Frame: Baseline to PET ]
3. Percent Change from Baseline in LDL-C in Cohort 2 [ Time Frame: Baseline to PET ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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

Contacts and Locations

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  Show 131 Study Locations

Sponsors and Collaborators

Kastle Therapeutics, LLC

Investigators

Study Director:	Medical Monitor	Genzyme, a Sanofi Company

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Tragante V, Asselbergs FW, Swerdlow DI, Palmer TM, Moore JH, de Bakker PI, Keating BJ, Holmes MV. Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk. Hum Genet. 2016 May;135(5):453-67. doi: 10.1007/s00439-016-1647-9. Epub 2016 Mar 5.

Responsible Party:	Kastle Therapeutics, LLC
ClinicalTrials.gov Identifier:	NCT01475825 History of Changes
Other Study ID Numbers:	MIPO3801011; 2011-001480-42 ( EudraCT Number ); EFC12875 ( Other Identifier: Sanofi )
First Posted:	November 21, 2011
Last Update Posted:	August 3, 2016
Last Verified:	August 2016

Additional relevant MeSH terms:

Hypercholesterolemia; Hyperlipoproteinemia Type II; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors	Genetic Diseases, Inborn; Hyperlipoproteinemias; Mipomersen; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents