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

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ClinicalTrials.gov Identifier: NCT00706849
Recruitment Status : Completed
First Posted : June 30, 2008
Results First Posted : March 21, 2013
Last Update Posted : September 9, 2016
Sponsor:
Collaborator:
Ionis Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Kastle Therapeutics, LLC

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).

Condition or disease Intervention/treatment Phase
Heterozygous Familial Hypercholesterolemia Coronary Artery Disease Drug: mipomersen sodium Drug: placebo Phase 3

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.


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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 124 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : July 2008
Actual Primary Completion Date : December 2009
Actual Study Completion Date : May 2010


Arm Intervention/treatment
Experimental: Mipomersen
Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.
Drug: mipomersen sodium
200 mg /mL
Other Names:
  • ISIS 301012
  • Kynamro™

Placebo Comparator: Placebo
Participants received a placebo subcutaneous injection once a week for 26 weeks.
Drug: placebo
1 mL matching placebo




Primary Outcome Measures :
  1. Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    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.

  2. LDL Cholesterol at Baseline and at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.


Secondary Outcome Measures :
  1. Percent Change From Baseline in Apolipoprotein B at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    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.

  2. Apolipoprotein B at Baseline and at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  3. Percent Change From Baseline in Total Cholesterol at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    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.

  4. Total Cholesterol at Baseline and at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  5. Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    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.

  6. Non-High-Density Lipoprotein Cholesterol at Baseline and at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.


Other Outcome Measures:
  1. Percent Change From Baseline in Triglycerides at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    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.

  2. Triglycerides at Baseline and at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  3. Percent Change From Baseline in Lipoprotein (a) at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    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.

  4. Lipoprotein (a) at Baseline and at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  5. Percent Change From Baseline in Very Low Density Lipoprotein Cholesterol at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    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.

  6. Very Low Density Lipoprotein at Baseline and at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  7. Percent Change From Baseline in the Ratio of LDL Cholesterol to HDL Cholesterol at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    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.

  8. Ratio of LDL Cholesterol to HDL Cholesterol at Baseline and at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  9. Percent Change From Baseline in Apolipoprotein A1 at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    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.

  10. Apolipoprotein A1 at Baseline and at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  11. Percent Change From Baseline in High-Density Lipoprotein Cholesterol at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    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.

  12. High-Density Lipoprotein Cholesterol at Baseline and at the 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; Week 28 or the post-baseline visit closest to 14 days after the last dose). ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.



Information from the National Library of Medicine

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00706849


  Show 48 Study Locations
Sponsors and Collaborators
Kastle Therapeutics, LLC
Ionis Pharmaceuticals, Inc.
Investigators
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Study Director: Medical Monitor Genzyme, a Sanofi Company

Publications of Results:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Kastle Therapeutics, LLC
ClinicalTrials.gov Identifier: NCT00706849     History of Changes
Other Study ID Numbers: 301012-CS7
First Posted: June 30, 2008    Key Record Dates
Results First Posted: March 21, 2013
Last Update Posted: September 9, 2016
Last Verified: August 2016
Keywords provided by Kastle Therapeutics, LLC:
familial hypercholesterolemia
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Hyperlipoproteinemia Type II
Hypercholesterolemia
Heart Diseases
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Hyperlipidemias
Dyslipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Hyperlipoproteinemias
Mipomersen
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents