Efficacy and Safety Study of ISIS 301012 (Mipomersen) as Add-on in Familial Hypercholesterolemic Patients With Coronary Artery Disease

Coronary Artery Disease Clinical Trial

— RADICHOL II  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00706849
• Other study ID #: 301012-CS7
• Status: Completed
• Phase: Phase 3
• First received: June 26, 2008
• Last updated: December 2, 2013
• Start date: July 2008
• Est. completion date: May 2010

Study information

• Verified date: December 2013
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationCanada: Health Canada
• Study type: Interventional

Clinical Trial 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).

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 124
• Est. completion date: May 2010
• Est. primary completion date: December 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Heterozygous Familial Hypercholesterolemia
• Hypercholesterolemia
• Hyperlipoproteinemia Type II
• Myocardial Ischemia

Intervention

Drug:
• mipomersen sodium
200 mg /mL
• placebo
1 mL matching placebo

Locations

Country	Name	City	State
United States	ResEvo, LLC	Cuyahoga Falls	Ohio
United States	The Rogosin Institute Comprehensive Lipid Control Center	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company	Ionis Pharmaceuticals, Inc.

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (1)

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 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	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).	No
Other	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).	No
Other	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).	No
Other	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).	No
Other	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).	No
Other	Very Low Density Lipoprotein 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).	No
Other	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).	No
Other	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).	No
Other	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).	No
Other	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).	No
Other	Percent Change From Baseline in High-Density Lipoprotein Cholesterol 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).	No
Other	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).	No
Primary	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. 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. 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).	No
Primary	LDL 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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No
Secondary	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).	No