Safety and Efficacy of Mipomersen in Patients With Severe Hypercholesterolemia on a Maximally Tolerated Lipid-Lowering Regimen and Who Are Not on Apheresis

A Prospective Randomized, Double-Blind, Placebo-Controlled Study to Assess the Safety and Efficacy of Mipomersen in Patients With Severe Hypercholesterolemia on a Maximally Tolerated Lipid-Lowering Regimen and Who Are Not on Apheresis

The purpose of the study is to evaluate the safety and efficacy of dosing with mipomersen for 26 weeks in treating severely hypercholesterolemic patients who are on a maximally tolerated lipid-lowering regimen and who are not on apheresis.

Study Overview

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

Detailed Description

Hypercholesterolemia is characterized by markedly elevated low density lipoproteins (LDL). Elevated LDL is a major risk factor for coronary heart disease (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 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. The purpose of this study is to determine whether mipomersen safely and effectively lowers LDL-C in severely hypercholesterolemic patients who are on a maximally tolerated lipid-lowering regimen and who are not on apheresis.

• Study Type: Interventional
• Enrollment (Actual): 58
• Phase: Phase 3

Contacts and Locations

Study Locations

• Canada
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1M5
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
    • Montreal, Quebec, Canada, H1T 1C8
• Czech Republic
  • Hardec Kralove, Czech Republic, 500 05
  • Pilsen, Czech Republic, 305 99
  • Praha, Czech Republic, 128 08
  • Uherske Hradiste, Czech Republic, 686 68
• Germany
  • Berlin, Germany, 13353
  • Freiburg, Germany, 79106
  • Heidelberg, Germany, 69120
  • Koln (Lindenthal), Germany, 50937
• South Africa
  • Cape Town, South Africa, 7500
  • Cape Town, South Africa, 7925
  • Gauteng, South Africa, 0157
  • Pretoria, South Africa, 0002
• United Kingdom
  • London, United Kingdom, SE1 7EH
  • Manchester, United Kingdom, MI3 9WL
  • Surrey
    • Guildford, Surrey, United Kingdom, GU2 7XX
• United States
  • Florida
    • Jupiter, Florida, United States, 33458
    • Winter Park, Florida, United States, 32792
  • Georgia
    • Atlanta, Georgia, United States, 30338
  • Kansas
    • Kansas City, Kansas, United States, 66160
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
  • Missouri
    • St Louis, Missouri, United States, 63104
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
  • Ohio
    • Cincinnati, Ohio, United States, 45212
  • South Carolina
    • Aiken, South Carolina, United States, 29801

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Fasting LDL-C ≥200 mg/dL (5.1 mmol/L) at screening and the presence of at least 1 of the following criteria:

  • Myocardial infarction (MI)
  • Percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG)
  • Coronary artery disease documented by angiography or any other accepted imaging technique
  • Positive exercise test (≥1 mm ST-depression at maximal exercise or test terminated because of angina) or a perfusion defect (e.g., thallium or single photon emission computed tomography)
  • Other clinical atherosclerotic diseases: peripheral artery disease, symptomatic carotid artery disease, abdominal aortic aneurysm
  • Or, if alternative above were not met, fasting LDL-C ≥300 mg/dL (7.8 mmol/L)
• On stable, maximally tolerated statin therapy for 8 weeks
• On stable, medication from an additional class of hypolipidemic agents 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, 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 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
Placebo Comparator: Placebo; Weekly subcutaneous injections for 26 weeks	Drug: Placebo; 1 mL weekly subcutaneous injections for 26 weeks
Experimental: Mipomersen; 200 mg weekly subcutaneous injections for 26 weeks	Drug: Mipomersen; 200 mg (1 mL), weekly subcutaneous injections for 26 weeks; Other Names: ISIS 301012; Kynamro™; Mipomersen sodium

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LDL-C at Baseline and the Primary Efficacy Time Point (PET)	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point	LDL-C 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. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point	Apo-B was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET)	Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET)	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET)	Non-HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET)	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Apo-B at Baseline and the Primary Efficacy Time Point (PET)	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage Change From Baseline in Triglycerides at Primary Efficacy Time Point (PET)	Triglycerides were measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Triglycerides at Baseline and the Primary Efficacy Time Point (PET)	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Percentage Change From Baseline in Lipoprotein(a) at Primary Efficacy Time Point (PET)	Lipoprotein(a) was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET)	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Percentage Change From Baseline in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) at Primary Efficacy Time Point (PET)	VLDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
VLDL-C at Baseline and the Primary Efficacy Time Point (PET)	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol (LDL-C) to High-density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET)	LDL-C and HDL-C were measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET)	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Percent Change From Baseline in Apolipoprotein A1 (Apo-A1) at Primary Efficacy Time Point (PET)	Apo-A1 was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Apo-A1 at Baseline and the Primary Efficacy Time Point (PET)	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Percentage Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET)	HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
HDL-C at Baseline and the Primary Efficacy Time Point (PET)	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28

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.
• 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.
• McGowan MP, Tardif JC, Ceska R, Burgess LJ, Soran H, Gouni-Berthold I, Wagener G, Chasan-Taber S. Randomized, placebo-controlled trial of mipomersen in patients with severe hypercholesterolemia receiving maximally tolerated lipid-lowering therapy. PLoS One. 2012;7(11):e49006. doi: 10.1371/journal.pone.0049006. Epub 2012 Nov 13.

Study record dates

Study Major Dates

• Study Start: January 1, 2009
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: November 19, 2008
• First Submitted That Met QC Criteria: November 19, 2008
• First Posted (Estimate): November 20, 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: MIPO3500108; 2008-006020-53 (EudraCT Number)