Efficacy and Safety Study of ISIS 301012 (Mipomersen) as Add-on in Familial Hypercholesterolemic Patients With Coronary Artery Disease (RADICHOL II)

A Randomized, Double-Blind, Placebo-Controlled Study to Assess Efficacy and Safety of ISIS 301012 as Add-on Therapy in Heterozygous Familial Hypercholesterolemia Subjects With Coronary Artery Disease

The purpose of this study is to determine whether mipomersen safely and effectively lowers low-density lipoprotein cholesterol (LDL-C) in patients with Heterozygous Familial Hypercholesterolemia (HeFH) and coronary artery disease (CAD) who are already on a stable dose of other lipid-lowering agents (including maximally tolerated statin therapy).

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Heterozygous Familial Hypercholesterolemia
• Intervention / Treatment: Drug: mipomersen sodium; Drug: placebo

Detailed Description

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipoprotein metabolism characterized by markedly elevated LDL-C, premature onset of atherosclerosis and development of xanthomata. Patients with heterozygous familial hypercholesterolemia typically have total plasma cholesterol between 350 to 550 mg/dL and disease onset in their third and fourth decade.

Mipomersen (ISIS 301012) 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 (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 coronary heart disease (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.

This study consisted of a 26-week treatment period and a 24-week post-treatment follow-up period (with the exception of patients who enrolled in the open-label extension study [Study 301012-CS6; NCT00694109]). The treatment period spanned the time during which the study treatment was administered until the later of the primary efficacy time point (PET) or 14 days beyond the last day of study drug administration. The post-treatment follow-up period began the day after completion of the treatment period and ended on the day of the patient's last contact date within the study.

Following treatment and Week 28 evaluations, eligible patients who tolerated study drug could elect to enroll in an open-label extension study (301012-CS6). Patients who were not eligible for or who elected not to enroll in the open-label extension study and patients who discontinued during the 26-week treatment period were followed in this study for an additional 24 weeks from administration of the last dose of study drug.

• Study Type: Interventional
• Enrollment (Actual): 124
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2E 7C5
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 1Y6
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1R9
  • Ontario
    • London, Ontario, Canada, N6A 5K8
    • Toronto, Ontario, Canada, M5G 2C4
    • Toronto, Ontario, Canada, M5C 2T2
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
    • Montreal, Quebec, Canada, H1T 1C8
    • Montreal, Quebec, Canada, H2W 1R7
    • Sherbrooke, Quebec, Canada, J1H 5N4
    • St. Foy, Quebec, Canada, G1V 4M6
• United States
  • California
    • La Jolla, California, United States, 92093
    • Los Angeles, California, United States, 90048
    • Mission Viejo, California, United States, 92691
    • Newport Beach, California, United States, 92260
    • Santa Ana, California, United States, 92705
    • Thousand Oaks, California, United States, 91360
  • Connecticut
    • Bridgeport, Connecticut, United States, 06606
  • Florida
    • Melbourne, Florida, United States, 32901
    • Pensacola, Florida, United States, 32514
  • Illinois
    • Chicago, Illinois, United States, 60610
    • Naperville, Illinois, United States, 60540
  • Kansas
    • Kansas City, Kansas, United States, 66160
  • Maine
    • Biddeford, Maine, United States, 04005
    • Scarborough, Maine, United States, 04074
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5853
  • Missouri
    • St. Louis, Missouri, United States, 63110
  • Nevada
    • Las Vegas, Nevada, United States, 89144
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
  • New York
    • New York, New York, United States, 10032
    • New York, New York, United States, 10065
      • The Rogosin Institute Comprehensive Lipid Control Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
    • Charlotte, North Carolina, United States, 28211
    • Durham, North Carolina, United States, 27710
  • Ohio
    • Cincinnati, Ohio, United States, 45212
    • Cuyahoga Falls, Ohio, United States, 44223
      • ReSevo, LLC
    • Franklin, Ohio, United States, 45005
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73120
  • Oregon
    • Portland, Oregon, United States, 97239
  • Tennessee
    • Nashville, Tennessee, United States, 37232
  • Texas
    • Dallas, Texas, United States, 75226
    • Dallas, Texas, United States, 75220
    • Grapevine, Texas, United States, 76051
    • Houston, Texas, United States, 77093
    • San Antonio, Texas, United States, 78229
  • Utah
    • Salt Lake City, Utah, United States, 84108
  • Washington
    • Seattle, Washington, United States, 98104

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Diagnosis of Heterozygous Familial Hypercholesterolemia (HeFH)
• Diagnosis of Coronary Artery Disease (CAD)
• Stable lipid-lowering therapy for 12 weeks
• On maximally tolerated statin therapy with at least 1 statin at a dose greater than zero, per Investigator judgment
• Stable low-fat diet for 8 weeks
• Stable weight for 6 weeks

Exclusion Criteria:

• Significant health problems in recent past including heart attack, stroke, coronary syndrome, unstable angina, heart failure, significant arrhythmia, orthostatic hypotension, uncontrolled hypertension, blood disorders, liver disease, cancer, or digestive problems
• Receiving apheresis treatment or last apheresis treatment within 8 weeks

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Mipomersen; Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.	Drug: mipomersen sodium; 200 mg /mL; Other Names: ISIS 301012; Kynamro™
Placebo Comparator: Placebo; Participants received a placebo subcutaneous injection once a week for 26 weeks.	Drug: placebo; 1 mL matching placebo

What is the study measuring?

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. 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. 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).
LDL 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).

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).

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Triglycerides at the Primary Efficacy Time Point	Triglycerides were 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).
Triglycerides 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 Lipoprotein (a) at the Primary Efficacy Time Point	Lipoprotein (a) 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).
Lipoprotein (a) 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 Very Low Density Lipoprotein Cholesterol at the Primary Efficacy Time Point	Very low density lipoprotein (VLDL) 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).
Very Low Density Lipoprotein 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 the Ratio of LDL Cholesterol to HDL Cholesterol at the Primary Efficacy Time Point	The ratio of low-density lipoprotein (LDL) cholesterol to high-density lipoprotein (HDL) cholesterol was measured at Baseline and 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).
Ratio of LDL Cholesterol to HDL 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 Apolipoprotein A1 at the Primary Efficacy Time Point	Apolipoprotein A1 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 A1 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 High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point	High-density lipoprotein cholesterol (HDL-C) 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).
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).

Collaborators and Investigators

• Sponsor: Kastle Therapeutics, LLC
• Collaborators: Ionis Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• Duell PB, Santos RD, Kirwan BA, Witztum JL, Tsimikas S, Kastelein JJP. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol. 2016 Jul-Aug;10(4):1011-1021. doi: 10.1016/j.jacl.2016.04.013. Epub 2016 May 9.
• Stein EA, Dufour R, Gagne C, Gaudet D, East C, Donovan JM, Chin W, Tribble DL, McGowan M. Apolipoprotein B synthesis inhibition with mipomersen in heterozygous familial hypercholesterolemia: results of a randomized, double-blind, placebo-controlled trial to assess efficacy and safety as add-on therapy in patients with coronary artery disease. Circulation. 2012 Nov 6;126(19):2283-92. doi: 10.1161/CIRCULATIONAHA.112.104125. Epub 2012 Oct 11.
• Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen-Thiessen E, Tsimikas S. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler Thromb Vasc Biol. 2015 Mar;35(3):689-99. doi: 10.1161/ATVBAHA.114.304549. Epub 2015 Jan 22.

Study record dates

Study Major Dates

• Study Start: July 1, 2008
• Primary Completion (Actual): December 1, 2009
• Study Completion (Actual): May 1, 2010

Study Registration Dates

• First Submitted: June 26, 2008
• First Submitted That Met QC Criteria: June 27, 2008
• First Posted (Estimate): June 30, 2008

Study Record Updates

• Last Update Posted (Estimate): September 9, 2016
• Last Update Submitted That Met QC Criteria: August 1, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: familial hypercholesterolemia
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Hypercholesterolemia; Hyperlipoproteinemia Type II; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Mipomersen
• Other Study ID Numbers: 301012-CS7