Safety and Efficacy Study of ISIS 301012 (Mipomersen) Administration in High Risk Statin Intolerant Subjects (ASSIST)

This study has been completed.
Sponsor:
Collaborator:
Isis Pharmaceuticals
Information provided by (Responsible Party):
Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier:
NCT00707746
First received: June 27, 2008
Last updated: February 25, 2013
Last verified: February 2013
  Purpose

The purpose of this study is to determine safety and efficacy of mipomersen (ISIS 301012) in the reduction of total cholesterol, low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apoB) in high risk subjects intolerant to statins.


Condition Intervention Phase
Metabolic Diseases
Hyperlipidemias
Metabolic Disorder
Hypercholesterolemia
Dyslipidemias
Lipid Metabolism Disorders
Drug: mipomersen
Drug: placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double-Blind, Placebo-Controlled Study to Assess Safety and Efficacy of ISIS 301012 Administration in High Risk Statin Intolerant Subjects

Resource links provided by NLM:


Further study details as provided by Genzyme, a Sanofi Company:

Primary Outcome Measures:
  • 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). ] [ Designated as safety issue: No ]
    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. The primary efficacy time point was the post-baseline visit closest to 14 days after the last dose of study treatment.

  • Low-density Lipoprotein Cholesterol at Baseline and 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). ] [ Designated as safety issue: No ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  • Summary of Participants With Adverse Events [ Time Frame: Pre-treatment (prior to first dose), On-treatment (Day 1 to week 28), Post-treatment (Week 28-52) ] [ Designated as safety issue: Yes ]

    The on-treatment time frame spanned the time during which the study drug was administered until the later of the primary efficacy time point and 14 days beyond the last study drug date.

    Adverse events (AEs) were considered related if assessed by the Investigator as possibly, probably or definitely related to study drug.

    Severity was assessed as:

    • Mild-symptom barely noticeable to the patient or do not make the patient uncomfortable;
    • Moderate-symptom makes the patient uncomfortable, affects performance of daily activities;
    • Severe-symptom causes the patient severe discomfort, may cause cessation of treatment with the study drug.

    Serious AEs (SAEs) are those that resulted in death, were life-threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability/incapacity, congenital anomaly, or resulted in an important medical event that may have jeopardized the patient or required medical or surgical intervention.



Secondary Outcome Measures:
  • 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). ] [ Designated as safety issue: No ]
    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.

  • 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). ] [ Designated as safety issue: No ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  • 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). ] [ Designated as safety issue: No ]
    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.

  • 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). ] [ Designated as safety issue: No ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  • 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). ] [ Designated as safety issue: No ]
    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.

  • 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). ] [ Designated as safety issue: No ]
    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:
  • 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). ] [ Designated as safety issue: No ]
    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.

  • 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). ] [ Designated as safety issue: No ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  • 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). ] [ Designated as safety issue: No ]
    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.

  • 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). ] [ Designated as safety issue: No ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  • 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). ] [ Designated as safety issue: No ]
    Very low 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.

  • Very Low 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). ] [ Designated as safety issue: No ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  • Percent Change From Baseline in the Ratio of Low-Density Lipoprotein Cholesterol to 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). ] [ Designated as safety issue: No ]
    The ratio of low-density lipoprotein (LDL) cholesterol to high-density lipoprotein (HDL) 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.

  • Ratio of Low-Density Lipoprotein Cholesterol to 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). ] [ Designated as safety issue: No ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  • 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). ] [ Designated as safety issue: No ]
    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.

  • 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). ] [ Designated as safety issue: No ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  • 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). ] [ Designated as safety issue: No ]
    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.

  • 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). ] [ Designated as safety issue: No ]
    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.


Enrollment: 34
Study Start Date: October 2008
Study Completion Date: January 2011
Primary Completion Date: August 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Placebo
1 mL placebo saline, weekly subcutaneous injections for 26 weeks
Drug: placebo
Other Name: placebo saline
Experimental: Mipomersen
200 mg (1 mL), weekly subcutaneous injections for 26 weeks
Drug: mipomersen
Other Names:
  • ISIS 301012
  • mipomersen sodium
  • Kynamro™

Detailed Description:

In humans, apoB is the principal apolipoprotein of the atherogenic lipoproteins, comprising very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL). ApoB messenger ribonucleic acid (mRNA) is abundantly present in the liver. Within the endoplasmatic reticulum, apoB requires lipidation by microsomal triglyceride transfer protein, which allows apoB to be incorporated in the VLDL particle within the lumen of the endoplasmatic reticulum. Non-lipidated apoB is readily degraded via ubiquitination. Notably, apoB within the VLDL particle is obligatory for hepatic secretion of VLDL. ApoB remains present within the VLDL-metabolism pathway, from secretion to clearance of the end product LDL by the liver LDL receptor. As a consequence, apoB reliably reflects the total burden of atherogenic lipoproteins. Thus, apoB carries strong prognostic value for cardiovascular events, which exceeds the predictive value of LDL-C. Conversely, decreased levels of apoB (e.g. in familial hypobetalipoproteinemia) have been associated with reduced levels of atherosclerosis. These genetic observations have prompted interest in pharmacologic inhibition of apoB synthesis.

Mipomersen (ISIS 301012) is an antisense drug targeted to human apoB, the principal apolipoprotein of LDL and its metabolic precursor, VLDL. Mipomersen (ISIS 301012) is complementary to the coding region of the mRNA for apoB, binding by Watson and Crick base pairing. The hybridization (binding) of mipomersen (ISIS 301012) to the cognate mRNA results in Ribonuclease (RNase) H-mediated degradation of the cognate mRNA, thus inhibiting translation of the apoB protein.

This was a randomized, double-blind, placebo-controlled Phase 2 study to assess the safety and efficacy of mipomersen administration in high-risk statin-intolerant patients with hypercholesterolemia. This study consisted of a ≤3-week screening period, 26 weeks of treatment, and a 24-week post-treatment follow-up period.

Eligible patients were randomized in a 2:1 ratio to receive mipomersen 200 mg or matching volume placebo subcutaneous (SC) injections weekly.

Following the screening visit, eligible patients returned to the study center for clinical evaluation every week for study drug administration and assessments.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Diagnosis of statin intolerance
  • Diagnosis of Coronary Artery Disease (CAD)
  • Diagnosis of hypercholesterolemia
  • Stable weight for > 6 weeks

Exclusion Criteria:

  • Significant health problems in the recent past (≤24 weeks) including heart attack, heart surgery, heart failure, uncontrolled hypothyroidism, blood disorders, digestive problems, disease of central nervous system, cancer, liver or renal disease
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00707746

Locations
Netherlands
Amsterdam, Netherlands, 1105AZ
Sponsors and Collaborators
Genzyme, a Sanofi Company
Isis Pharmaceuticals
Investigators
Study Director: Medical Monitor Genzyme, a Sanofi Company
  More Information

No publications provided by Genzyme, a Sanofi Company

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Genzyme, a Sanofi Company
ClinicalTrials.gov Identifier: NCT00707746     History of Changes
Other Study ID Numbers: 301012-CS19, 2007-005140-24
Study First Received: June 27, 2008
Results First Received: February 25, 2013
Last Updated: February 25, 2013
Health Authority: Netherlands: Ministry of Health, Welfare and Sport

Keywords provided by Genzyme, a Sanofi Company:
statin intolerant
hypercholesterolemia

Additional relevant MeSH terms:
Disease
Dyslipidemias
Hypercholesterolemia
Hyperlipidemias
Lipid Metabolism Disorders
Metabolic Diseases
Sphingolipidoses
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Lipid Metabolism, Inborn Errors
Lipidoses
Lysosomal Storage Diseases
Lysosomal Storage Diseases, Nervous System
Metabolism, Inborn Errors
Nervous System Diseases
Pathologic Processes
Mipomersen
Anticholesteremic Agents
Antimetabolites
Diagnostic Uses of Chemicals
Hypolipidemic Agents
Lipid Regulating Agents
Molecular Mechanisms of Pharmacological Action
Molecular Probes
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014