Safety and Efficacy of Mipomersen (ISIS 301012) As Add-on Therapy in High Risk Hypercholesterolemic Patients

A Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) as Add-on Therapy in High Risk Hypercholesterolemic Patients

The purpose of this study is to evaluate the safety and efficacy of dosing with mipomersen for 26 weeks in patients with high cholesterol who are on a maximally tolerated dose of statin and who have a diagnosis that puts them at least at high risk of coronary heart disease (CHD).

Study Overview

• Status: Completed
• Conditions: Hypercholesterolemia; Coronary Heart Disease
• Intervention / Treatment: Drug: Placebo; Drug: Mipomersen sodium

Detailed Description

Hypercholesterolemia is characterized by markedly elevated low density lipoproteins (LDL). Elevated LDL is a major risk factor for CHD.

Mipomersen 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 (LDL-C) (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 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. The purpose of this study is to determine whether mipomersen safely and effectively lowers LDL-C in patients with high cholesterol who are at high risk for CHD and who are already on the maximally tolerated dose of statin.

This study consisted of a 26-week treatment period and a 24-week post-treatment follow-up period. Participants who finished treatment or who discontinued prematurely from the study for any reason were assessed for safety for 24 weeks after the last study drug dose.

• Study Type: Interventional
• Enrollment (Actual): 158
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
    • Birmingham, Alabama, United States, 35209
    • Huntsville, Alabama, United States, 35801
    • Muscle Shoals, Alabama, United States, 35662
  • Arizona
    • Litchfield Park, Arizona, United States, 85340
  • California
    • Beverly Hills, California, United States, 90211
    • Escondido, California, United States, 92025
    • Los Angeles, California, United States, 90025
    • Mission Viejo, California, United States, 92691
    • Newport Beach, California, United States, 92660
    • San Diego, California, United States, 92117
    • Santa Rosa, California, United States, 95405
    • Thousand Oaks, California, United States, 91360
    • Westlake Village, California, United States, 91361
  • Florida
    • Aventura, Florida, United States, 33180
    • Inverness, Florida, United States, 34452
    • Jacksonville, Florida, United States, 32216
    • Longwood, Florida, United States, 32779
    • Miami, Florida, United States, 33143
    • Miami, Florida, United States, 33169
    • New Port Richey, Florida, United States, 34652
    • Pembroke Pines, Florida, United States, 33026
    • Pensacola, Florida, United States, 32514
    • Ponte Verda, Florida, United States, 32081
    • Port Orange, Florida, United States, 32127
  • Georgia
    • Sandy Springs, Georgia, United States, 30328
  • Illinois
    • Chicago, Illinois, United States, 60654
    • Chicago, Illinois, United States, 60624
    • Chicago, Illinois, United States, 60607
  • Indiana
    • Bloomingtom, Indiana, United States, 47403
    • Evansville, Indiana, United States, 47714
    • Indianapolis, Indiana, United States, 46260
    • Indianapolis, Indiana, United States, 46254
  • Kentucky
    • Louisville, Kentucky, United States, 40213
  • Maryland
    • Baltimore, Maryland, United States, 21209
  • Massachusetts
    • Brockton, Massachusetts, United States, 02301
    • New Bedford, Massachusetts, United States, 02740
  • Minnesota
    • Edina, Minnesota, United States, 55435
  • Missouri
    • Kansas City, Missouri, United States, 64111
  • New Jersey
    • Berlin, New Jersey, United States, 08009
  • New York
    • Johnson City, New York, United States, 13790
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
    • Greenville, North Carolina, United States, 27834
    • Wilson, North Carolina, United States, 27893
  • Ohio
    • Cincinnati, Ohio, United States, 45219
    • Mentor, Ohio, United States, 44060
  • Oklahoma
    • Norman, Oklahoma, United States, 73069
    • Tulsa, Oklahoma, United States, 74136
  • Oregon
    • Portland, Oregon, United States, 97239
  • Pennsylvania
    • Lansdale, Pennsylvania, United States, 19446
  • South Carolina
    • Murrells Inlet, South Carolina, United States, 29576
    • Simpsonville, South Carolina, United States, 29681
    • Spartanburg, South Carolina, United States, 29303
  • South Dakota
    • Rapid City, South Dakota, United States, 57702
  • Texas
    • Dallas, Texas, United States, 75251
    • Dallas, Texas, United States, 75220
    • Grapevine, Texas, United States, 76051
    • Houston, Texas, United States, 77030
    • Houston, Texas, United States, 77074
    • Houston, Texas, United States, 77093
    • San Antonio, Texas, United States, 78229
  • Washington
    • Olympia, Washington, United States, 98502

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 hypercholesterolemia (LDL-C ≥ 100 mg/dL)
• At high risk of CHD
• On stable, maximally tolerated statin therapy for 8 weeks
• On stable, low fat diet for 12 weeks
• 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, liver disease, cancer, type I diabetes.

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 placebo subcutaneous injection once a week for 26 weeks.	Drug: Placebo; 1 mL matching placebo (i.e., vehicle consisting of 9 mg of sodium chloride, 0.004 mg of riboflavin, filled to 1 mL with water).

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. LDL-C was obtained using Friedewald's calculation for patients with triglycerides ≤400 mg/dL and was directly measured by the central laboratory using ultracentrifugation for patients with triglycerides >400 mg/dL. 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).
Low-density Lipoprotein Cholesterol (LDL-C) 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).
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).
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).
Percent Change From Baseline in High Density Lipoprotein Cholesterol (HDL-C) 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).
Very Low 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

• 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.
• Thomas GS, Cromwell WC, Ali S, Chin W, Flaim JD, Davidson M. Mipomersen, an apolipoprotein B synthesis inhibitor, reduces atherogenic lipoproteins in patients with severe hypercholesterolemia at high cardiovascular risk: a randomized, double-blind, placebo-controlled trial. J Am Coll Cardiol. 2013 Dec 10;62(23):2178-84. doi: 10.1016/j.jacc.2013.07.081. Epub 2013 Sep 4.

Study record dates

Study Major Dates

• Study Start: November 1, 2008
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: October 8, 2008
• First Submitted That Met QC Criteria: October 8, 2008
• First Posted (Estimate): October 9, 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

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Heart Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Hypercholesterolemia; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Mipomersen
• Other Study ID Numbers: 301012-CS12