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

• ClinicalTrials.gov Identifier: NCT00794664
• Recruitment Status: Completed
• First Posted: November 20, 2008
• Results First Posted: March 21, 2013
• Last Update Posted: September 9, 2016
• Sponsor: Kastle Therapeutics, LLC
• Collaborator: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Kastle Therapeutics, LLC

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hypercholesterolemia; Coronary Heart Disease	Drug: Mipomersen; Drug: Placebo	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 58 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: January 2009
• Actual Primary Completion Date: May 2010
• Actual Study Completion Date: October 2010

Arms and Interventions

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; Mipomersen sodium; Kynamro™

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   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.
2. LDL-C at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

Secondary Outcome Measures :

1. Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point [ Time Frame: 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 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.
2. Apo-B at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
3. Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET) [ Time Frame: 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 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.
4. Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
5. Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET) [ Time Frame: 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 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.
6. Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

Other Outcome Measures:

1. Percentage Change From Baseline in Triglycerides at Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   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.
2. Triglycerides at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
3. Percentage Change From Baseline in Lipoprotein(a) at Primary Efficacy Time Point (PET) [ Time Frame: 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) 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.
4. Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
5. Percentage Change From Baseline in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) at Primary Efficacy Time Point (PET) [ Time Frame: 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 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.
6. VLDL-C at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
7. 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) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   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.
8. Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
   The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
9. Percent Change From Baseline in Apolipoprotein A1 (Apo-A1) at Primary Efficacy Time Point (PET) [ Time Frame: 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 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.
10. Apo-A1 at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
11. Percentage Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET) [ Time Frame: 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 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.
12. HDL-C at Baseline and the Primary Efficacy Time Point (PET) [ Time Frame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 ]
    The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Florida

Jupiter, Florida, United States, 33458

Winter Park, Florida, United States, 32792

United States, Georgia

Atlanta, Georgia, United States, 30338

United States, Kansas

Kansas City, Kansas, United States, 66160

United States, Massachusetts

Boston, Massachusetts, United States, 02114

United States, Missouri

St Louis, Missouri, United States, 63104

United States, New Hampshire

Concord, New Hampshire, United States, 03301

United States, Ohio

Cincinnati, Ohio, United States, 45212

United States, South Carolina

Aiken, South Carolina, United States, 29801

Canada, Manitoba

Winnipeg, Manitoba, Canada, R3A 1M5

Canada, 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

Guildford, Surrey, United Kingdom, GU2 7XX

London, United Kingdom, SE1 7EH

Manchester, United Kingdom, MI3 9WL

Sponsors and Collaborators

Kastle Therapeutics, LLC

Ionis Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor; Genzyme, a Sanofi Company

More Information

Publications of Results:

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.

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

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.

• Responsible Party: Kastle Therapeutics, LLC
• ClinicalTrials.gov Identifier: NCT00794664
• Other Study ID Numbers: MIPO3500108; 2008-006020-53 ( EudraCT Number )
• First Posted: November 20, 2008
• Results First Posted: March 21, 2013
• Last Update Posted: September 9, 2016
• Last Verified: August 2016

Additional relevant MeSH terms:

Heart Diseases; Coronary Disease; Coronary Artery Disease; Myocardial Ischemia; Hypercholesterolemia; Cardiovascular Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Metabolic Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Mipomersen; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents