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Completed

NCT Number: NCT00707746

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

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.

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Key information

Conditions

Metabolic Diseases Dyslipidemias Hypercholesterolemia Hyperlipidemias Lipid Metabolism Disorders Metabolic Disorder Nutritional and Metabolic Diseases

Age range

18 year and older

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 2

Primary location

Amsterdam, 1105AZ, Netherlands

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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

Treatment and study plan

mipomersen

Drug

Other names: ISIS 301012, mipomersen sodium, Kynamro™

Placebo

Drug

Other names: placebo saline

Primary outcomes

  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-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.

  2. 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).

    The primary efficacy time point (PET) was the post-baseline visit closest to 14 days after the last dose of study treatment.

  3. 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)

    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 outcomes

  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 outcomes

  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 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 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.

  7. 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).

    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.

  8. 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).

    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.

Sponsors and collaborators

Lead sponsor

Kastle Therapeutics, LLC

Industry

Collaborators

  • Ionis Pharmaceuticals, Inc.

Registry information

Official study title

A Randomized, Double-Blind, Placebo-Controlled Study to Assess Safety and Efficacy of ISIS 301012 Administration in High Risk Statin Intolerant Subjects

Acronym: ASSIST

Important dates

Study start
2008
Primary completion
2010
Study completion
2011
First posted
Jul 1, 2008
Registry last updated
Sep 9, 2016

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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