Clinical trial NCT00706849: Efficacy and Safety Study of ISIS 301012 (Mipomersen) as Add-on in Familial Hypercholesterolemic Patients With Coronary Artery Disease
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Heterozygous Familial Hypercholesterolemia
Coronary Artery Disease
Keywords: familial hypercholesterolemia
Lead sponsor: Kastle Therapeutics, LLC
Sponsor class: INDUSTRY
Collaborators: name: Ionis Pharmaceuticals, Inc.
First posted: 2008-06-30
Enrollment: 124
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 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).

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.

Eligibility criteria: 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

Primary outcomes:
measure: Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the Primary Efficacy Time Point
timeFrame: 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).
measure: LDL Cholesterol at Baseline and at the Primary Efficacy Time Point
timeFrame: 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 outcomes:
measure: Percent Change From Baseline in Apolipoprotein B at the Primary Efficacy Time Point
timeFrame: 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).
measure: Apolipoprotein B at Baseline and at the Primary Efficacy Time Point
timeFrame: 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).
measure: Percent Change From Baseline in Total Cholesterol at the Primary Efficacy Time Point
timeFrame: 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).
measure: Total Cholesterol at Baseline and at the Primary Efficacy Time Point
timeFrame: 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).
measure: Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point
timeFrame: 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).
measure: Non-High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point
timeFrame: 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 outcomes:
measure: Percent Change From Baseline in Triglycerides at the Primary Efficacy Time Point
timeFrame: 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).
measure: Triglycerides at Baseline and at the Primary Efficacy Time Point
timeFrame: 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).
measure: Percent Change From Baseline in Lipoprotein (a) at the Primary Efficacy Time Point
timeFrame: 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).
measure: Lipoprotein (a) at Baseline and at the Primary Efficacy Time Point
timeFrame: 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).
measure: Percent Change From Baseline in Very Low Density Lipoprotein Cholesterol at the Primary Efficacy Time Point
timeFrame: 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).
measure: Very Low Density Lipoprotein at Baseline and at the Primary Efficacy Time Point
timeFrame: 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).
measure: Percent Change From Baseline in the Ratio of LDL Cholesterol to HDL Cholesterol at the Primary Efficacy Time Point
timeFrame: 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).
measure: Ratio of LDL Cholesterol to HDL Cholesterol at Baseline and at the Primary Efficacy Time Point
timeFrame: 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).
measure: Percent Change From Baseline in Apolipoprotein A1 at the Primary Efficacy Time Point
timeFrame: 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).
measure: Apolipoprotein A1 at Baseline and at the Primary Efficacy Time Point
timeFrame: 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).
measure: Percent Change From Baseline in High-Density Lipoprotein Cholesterol at the Primary Efficacy Time Point
timeFrame: 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).
measure: High-Density Lipoprotein Cholesterol at Baseline and at the Primary Efficacy Time Point
timeFrame: 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).
Locations:
city: La Jolla
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Mission Viejo
country: United States
state: California
city: Newport Beach
country: United States
state: California
city: Santa Ana
country: United States
state: California
city: Thousand Oaks
country: United States
state: California
city: Bridgeport
country: United States
state: Connecticut
city: Melbourne
country: United States
state: Florida
city: Pensacola
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Naperville
country: United States
state: Illinois
city: Kansas City
country: United States
state: Kansas
city: Biddeford
country: United States
state: Maine
city: Scarborough
country: United States
state: Maine
city: Boston
country: United States
state: Massachusetts
city: Ann Arbor
country: United States
state: Michigan
city: St. Louis
country: United States
state: Missouri
city: Las Vegas
country: United States
state: Nevada
city: Concord
country: United States
state: New Hampshire
city: New York
country: United States
state: New York
city: New York
country: United States
facility: The Rogosin Institute Comprehensive Lipid Control Center
state: New York
city: Charlotte
country: United States
state: North Carolina
city: Charlotte
country: United States
state: North Carolina
city: Durham
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Cuyahoga Falls
country: United States
facility: ResEvo, LLC
state: Ohio
city: Franklin
country: United States
state: Ohio
city: Oklahoma City
country: United States
state: Oklahoma
city: Portland
country: United States
state: Oregon
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Dallas
country: United States
state: Texas
city: Grapevine
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Salt Lake City
country: United States
state: Utah
city: Seattle
country: United States
state: Washington
city: Calgary
country: Canada
state: Alberta
city: Vancouver
country: Canada
state: British Columbia
city: Winnipeg
country: Canada
state: Manitoba
city: London
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Toronto
country: Canada
state: Ontario
city: Chicoutimi
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Sherbrooke
country: Canada
state: Quebec
city: St. Foy
country: Canada
state: Quebec
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.
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.