Clinical trial NCT00794664: Safety and Efficacy of Mipomersen in Patients With Severe Hypercholesterolemia on a Maximally Tolerated Lipid-Lowering Regimen and Who Are Not on Apheresis
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypercholesterolemia
Coronary Heart Disease
Lead sponsor: Kastle Therapeutics, LLC
Sponsor class: INDUSTRY
Collaborators: name: Ionis Pharmaceuticals, Inc.
First posted: 2008-11-20
Enrollment: 58
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: LDL-C at Baseline and the Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Secondary outcomes:
measure: Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Apo-B at Baseline and the Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Other outcomes:
measure: Percentage Change From Baseline in Triglycerides at Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Triglycerides at Baseline and the Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Percentage Change From Baseline in Lipoprotein(a) at Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Lipoprotein(a) at Baseline and the Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Percentage Change From Baseline in Very-Low-Density Lipoprotein Cholesterol (VLDL-C) at Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: VLDL-C at Baseline and the Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: 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)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Ratio of LDL-C to HDL-C at Baseline and the Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Percent Change From Baseline in Apolipoprotein A1 (Apo-A1) at Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Apo-A1 at Baseline and the Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: Percentage Change From Baseline in High-Density Lipoprotein Cholesterol (HDL-C) at Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
measure: HDL-C at Baseline and the Primary Efficacy Time Point (PET)
timeFrame: Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28
Locations:
city: Jupiter
country: United States
state: Florida
city: Winter Park
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Kansas City
country: United States
state: Kansas
city: Boston
country: United States
state: Massachusetts
city: St Louis
country: United States
state: Missouri
city: Concord
country: United States
state: New Hampshire
city: Cincinnati
country: United States
state: Ohio
city: Aiken
country: United States
state: South Carolina
city: Winnipeg
country: Canada
state: Manitoba
city: Chicoutimi
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Hardec Kralove
country: Czech Republic
city: Pilsen
country: Czech Republic
city: Praha
country: Czech Republic
city: Uherske Hradiste
country: Czech Republic
city: Berlin
country: Germany
city: Freiburg
country: Germany
city: Heidelberg
country: Germany
city: Koln (Lindenthal)
country: Germany
city: Cape Town
country: South Africa
city: Cape Town
country: South Africa
city: Gauteng
country: South Africa
city: Pretoria
country: South Africa
city: Guildford
country: United Kingdom
state: Surrey
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.