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Trial record 14 of 19 for:    MIPOMERSEN

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

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ClinicalTrials.gov Identifier: NCT00707746
Recruitment Status : Completed
First Posted : July 1, 2008
Results First Posted : April 5, 2013
Last Update Posted : September 9, 2016
Sponsor:
Collaborator:
Ionis Pharmaceuticals, Inc.
Information provided by (Responsible Party):
Kastle Therapeutics, LLC

Tracking Information
First Submitted Date  ICMJE June 27, 2008
First Posted Date  ICMJE July 1, 2008
Results First Submitted Date  ICMJE February 25, 2013
Results First Posted Date  ICMJE April 5, 2013
Last Update Posted Date September 9, 2016
Study Start Date  ICMJE October 2008
Actual Primary Completion Date August 2010   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 25, 2013)
  • 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.
  • 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.
  • 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.
Original Primary Outcome Measures  ICMJE
 (submitted: June 30, 2008)
To determine safety and efficacy of ISIS 301012 in the reduction of total cholesterol, LDL-C, and a[poB in subjects intolerant to statins. [ Time Frame: Week 15 ]
Change History Complete list of historical versions of study NCT00707746 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: February 25, 2013)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Secondary Outcome Measures  ICMJE
 (submitted: June 30, 2008)
  • To determine percent change from baseline HDL-C, triglyceride, non-HDL-C, VLDL, Lp(a) and concentration. [ Time Frame: Week 15 ]
  • To determine the effect of ISIS 301012 on endothelial function (assessed by flow mediated dilatation) [ Time Frame: Week 15 ]
Current Other Pre-specified Outcome Measures
 (submitted: February 25, 2013)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Safety and Efficacy Study of ISIS 301012 (Mipomersen) Administration in High Risk Statin Intolerant Subjects
Official Title  ICMJE A Randomized, Double-Blind, Placebo-Controlled Study to Assess Safety and Efficacy of ISIS 301012 Administration in High Risk Statin Intolerant Subjects
Brief Summary 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.
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Metabolic Diseases
  • Hyperlipidemias
  • Metabolic Disorder
  • Hypercholesterolemia
  • Dyslipidemias
  • Lipid Metabolism Disorders
Intervention  ICMJE
  • Drug: mipomersen
    Other Names:
    • ISIS 301012
    • mipomersen sodium
    • Kynamro™
  • Drug: placebo
    Other Name: placebo saline
Study Arms  ICMJE
  • Placebo Comparator: Placebo
    1 mL placebo saline, weekly subcutaneous injections for 26 weeks
    Intervention: Drug: placebo
  • Experimental: Mipomersen
    200 mg (1 mL), weekly subcutaneous injections for 26 weeks
    Intervention: Drug: mipomersen
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 25, 2013)
34
Original Estimated Enrollment  ICMJE
 (submitted: June 30, 2008)
30
Actual Study Completion Date  ICMJE January 2011
Actual Primary Completion Date August 2010   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00707746
Other Study ID Numbers  ICMJE 301012-CS19
2007-005140-24 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Kastle Therapeutics, LLC
Study Sponsor  ICMJE Kastle Therapeutics, LLC
Collaborators  ICMJE Ionis Pharmaceuticals, Inc.
Investigators  ICMJE
Study Director: Medical Monitor Genzyme, a Sanofi Company
PRS Account Kastle Therapeutics, LLC
Verification Date August 2016

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP