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Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia

Primary Purpose

Lipid Metabolism, Inborn Errors, Hypercholesterolemia, Autosomal Dominant, Hyperlipidemias

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
mipomersen sodium
Sponsored by
Kastle Therapeutics, LLC
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Lipid Metabolism, Inborn Errors focused on measuring Familial Hypercholesterolemia, Heterozygous Familial Hypercholesterolemia, Homozygous Familial Hypercholesterolemia, ISIS 301012, mipomersen, Open Label Extension

Eligibility Criteria

12 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

- Satisfactory completion of dosing and Week 7 or Week 15 assessments (depending on the treatment and dose received) in their initial study (Protocol 301012-CS8 (NCT00280995) or 301012-CS9 (NCT00281008)).

Exclusion Criteria:

- Have a new condition or worsening of existing condition which in the opinion of the Investigator would make the patient unsuitable for enrollment, or could interfere with patient's participation in or completion of the study.

Sites / Locations

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Mipomersen 200 mg per week

Mipomersen 200 mg every other week

Arm Description

Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.

Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.

Outcomes

Primary Outcome Measures

Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)
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. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Low-density Lipoprotein Cholesterol (LDL-C) Over Time
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. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.

Secondary Outcome Measures

Percent Change From Baseline in Apolipoprotein B
Apolipoprotein B was measured in mg/dL. Samples were taken following an overnight fast. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Apolipoprotein B Over Time
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Percent Change From Baseline in Total Cholesterol
Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast.
Total Cholesterol Over Time
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol
Non-high-density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast.
Non-High-Density Lipoprotein Cholesterol Over Time
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Number of Participants With Treatment-Emergent Adverse Events (AEs)
AEs were considered as related if assessed by the Investigator as possibly, probably or definitely related to study drug. The severity of each event was assessed using the following categories: Mild (symptom(s) barely noticeable to the patient or do not make the patient uncomfortable); Moderate (symptom(s) of a sufficient severity to make the patient uncomfortable, performance of daily activities is influenced) or Severe (symptom(s) of a sufficient severity to cause 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 to prevent one of the outcomes listed above.
Percent Change From Baseline in Clinical Chemistry Parameters
Percent Change From Baseline in Hematology Parameters
Percent Change From Baseline in Blood Pressure
Percent Change From Baseline in Pulse Rate
Percent Change From Baseline in Respiratory Rate

Full Information

First Posted
May 22, 2007
Last Updated
August 1, 2016
Sponsor
Kastle Therapeutics, LLC
Collaborators
Ionis Pharmaceuticals, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT00477594
Brief Title
Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia
Official Title
An Open-Label Extension Study to Assess the Long-term Safety and Efficacy of Mipomersen in Subjects With Familial Hypercholesterolemia
Study Type
Interventional

2. Study Status

Record Verification Date
August 2016
Overall Recruitment Status
Completed
Study Start Date
May 2007 (undefined)
Primary Completion Date
March 2011 (Actual)
Study Completion Date
July 2011 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Kastle Therapeutics, LLC
Collaborators
Ionis Pharmaceuticals, Inc.

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to evaluate the safety and efficacy of extended dosing of mipomersen in patients with familial hypercholesterolemia on lipid-lowering therapy who have completed either the 301012-CS8 (NCT00280995) or 301012-CS9 (NCT00281008) clinical drug trials.
Detailed Description
Familial Hypercholesterolemia (FH) is an autosomal dominant metabolic disorder characterized by markedly elevated low density lipoprotein (LDL), premature onset of atherosclerosis, and development of xanthomata. There are two distinct subpopulations that have a high unmet medical need due to the lack of alternative therapy: homozygotes, who have two defective LDL receptor (LDL-R) genes, and heterozygotes with a history of cardiovascular disease (CVD) on maximally tolerated therapy. Treatment for FH is directed at lowering plasma levels of LDL-C. Mipomersen is an antisense drug targeted to human apolipoprotein B (apoB), the principal apolipoprotein of atherogenic LDL-C and its metabolic precursor, very low density lipoprotein (VLDL). Mipomersen is complimentary to the coding region of the messenger ribonucleic acid (mRNA) for apo-B. Inhibition of apo-B would be expected to impair VLDL synthesis and result in lowered levels of LDL-C. In early clinical trials, mipomersen has been shown to reduce levels of LDL-C to recommended target levels in some participants. This was an open-label extension study, which consisted of a ≤2-week screening period, up to 3 years of treatment with mipomersen, and a 24-week post-treatment follow-up period. Patients who participated in Cohorts A, B, or C in study 301012-CS9 were randomized in a 1:1 ratio to mipomersen 200 mg once a week (QW) or 200 mg mipomersen every other week (QOW) for up to 3 years. Patients randomized to mipomersen 200 mg QOW were allowed to receive mipomersen 200 mg QW at the Investigator's discretion after the first 52 weeks of the treatment period. Patients who participated in study 301012-CS8 or Cohort D of study 301012-CS9 received 200 mg mipomersen QW for up to 3 years.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Lipid Metabolism, Inborn Errors, Hypercholesterolemia, Autosomal Dominant, Hyperlipidemias, Metabolic Diseases, Hyperlipoproteinemia Type II, Metabolism, Inborn Errors, Genetic Diseases, Inborn, Infant, Newborn, Diseases, Metabolic Disorder, Congenital Abnormalities, Hypercholesterolemia, Hyperlipoproteinemias, Dyslipidemias, Lipid Metabolism Disorders
Keywords
Familial Hypercholesterolemia, Heterozygous Familial Hypercholesterolemia, Homozygous Familial Hypercholesterolemia, ISIS 301012, mipomersen, Open Label Extension

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
21 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Mipomersen 200 mg per week
Arm Type
Experimental
Arm Description
Participants received 200 mg mipomersen once a week by subcutaneous injection, for up to 3 years.
Arm Title
Mipomersen 200 mg every other week
Arm Type
Experimental
Arm Description
Participants received 200 mg mipomersen every other week by subcutaneous injection, for up to 3 years. Participants could receive mipomersen 200 mg once a week at the Investigator's discretion after the first 52 weeks of the treatment period.
Intervention Type
Drug
Intervention Name(s)
mipomersen sodium
Other Intervention Name(s)
ISIS 301012, Kynamro™
Intervention Description
200 mg/ml, in 1 ml solution for subcutaneous injection.
Primary Outcome Measure Information:
Title
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C)
Description
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. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104
Title
Low-density Lipoprotein Cholesterol (LDL-C) Over Time
Description
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. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104.
Secondary Outcome Measure Information:
Title
Percent Change From Baseline in Apolipoprotein B
Description
Apolipoprotein B was measured in mg/dL. Samples were taken following an overnight fast. For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104
Title
Apolipoprotein B Over Time
Description
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104.
Title
Percent Change From Baseline in Total Cholesterol
Description
Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast.
Time Frame
Baseline and Weeks 52 and 104.
Title
Total Cholesterol Over Time
Description
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104.
Title
Percent Change From Baseline in Non-High-Density Lipoprotein Cholesterol
Description
Non-high-density lipoprotein cholesterol was measured in mg/dL. Samples were taken following an overnight fast.
Time Frame
Baseline and Weeks 52 and 104.
Title
Non-High-Density Lipoprotein Cholesterol Over Time
Description
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104.
Title
Number of Participants With Treatment-Emergent Adverse Events (AEs)
Description
AEs were considered as related if assessed by the Investigator as possibly, probably or definitely related to study drug. The severity of each event was assessed using the following categories: Mild (symptom(s) barely noticeable to the patient or do not make the patient uncomfortable); Moderate (symptom(s) of a sufficient severity to make the patient uncomfortable, performance of daily activities is influenced) or Severe (symptom(s) of a sufficient severity to cause 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 to prevent one of the outcomes listed above.
Time Frame
2 years
Title
Percent Change From Baseline in Clinical Chemistry Parameters
Time Frame
Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Title
Percent Change From Baseline in Hematology Parameters
Time Frame
Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment
Title
Percent Change From Baseline in Blood Pressure
Time Frame
Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Title
Percent Change From Baseline in Pulse Rate
Time Frame
Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Title
Percent Change From Baseline in Respiratory Rate
Time Frame
Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.
Other Pre-specified Outcome Measures:
Title
Percent Change From Baseline in Triglycerides
Description
Triglycerides were measured in mg/dL. Samples were taken following an overnight fast.
Time Frame
Baseline and Weeks 52 and 104.
Title
Triglycerides Over Time
Description
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104.
Title
Percent Change From Baseline in Lipoprotein(a)
Description
Lipoprotein(a) was measured in mg/dL. Samples were taken following an overnight fast.
Time Frame
Baseline and Weeks 52 and 104.
Title
Lipoprotein(a) Over Time
Description
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104.
Title
Percent Change From Baseline in Very-Low-Density Lipoprotein (VLDL) Cholesterol
Description
Very-Low-Density Lipoprotein (VLDL) Cholesterol was measured in mg/dL. Samples were taken following an overnight fast.
Time Frame
Baseline and Weeks 52 and 104.
Title
Very-Low-Density Lipoprotein (VLDL) Cholesterol Over Time
Description
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104.
Title
Percent Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol
Time Frame
Baseline and Weeks 52 and 104.
Title
Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol Over Time
Description
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104.
Title
Percent Change From Baseline in Apolipoprotein A1
Description
Apolipoprotein A1 was measured in mg/dL. Samples were taken following an overnight fast.
Time Frame
Baseline and Weeks 52 and 104.
Title
Apolipoprotein A1 Over Time
Description
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104.
Title
Percent Change From Baseline in High-Density Lipoprotein Cholesterol
Description
High-Density Lipoprotein (HDL) Cholesterol was measured in mg/dL. Samples were taken following an overnight fast.
Time Frame
Baseline and Weeks 52 and 104.
Title
High-Density Lipoprotein Cholesterol Over Time
Description
For patients who were on placebo in the index study or who took their last dose of mipomersen ≥6 months prior to first dose in this study, Baseline is defined as the last measurement prior to first dose in this study. For participants who took their last dose of mipomersen less than 6 months before starting this study, Baseline is defined as the last measurement taken prior to receiving a first dose in the index study.
Time Frame
Baseline and Weeks 52 and 104.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
12 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: - Satisfactory completion of dosing and Week 7 or Week 15 assessments (depending on the treatment and dose received) in their initial study (Protocol 301012-CS8 (NCT00280995) or 301012-CS9 (NCT00281008)). Exclusion Criteria: - Have a new condition or worsening of existing condition which in the opinion of the Investigator would make the patient unsuitable for enrollment, or could interfere with patient's participation in or completion of the study.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Medical Monitor
Organizational Affiliation
Genzyme, a Sanofi Company
Official's Role
Study Director
Facility Information:
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60654
Country
United States
City
Auburn
State/Province
Maine
ZIP/Postal Code
04210
Country
United States
City
Biddeford
State/Province
Maine
ZIP/Postal Code
04005
Country
United States
City
Scarborough
State/Province
Maine
ZIP/Postal Code
04074
Country
United States
City
Cincinnati
State/Province
Ohio
ZIP/Postal Code
45212
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
20707601
Citation
Patel N, Hegele RA. Mipomersen as a potential adjunctive therapy for hypercholesterolemia. Expert Opin Pharmacother. 2010 Oct;11(15):2569-72. doi: 10.1517/14656566.2010.512006.
Results Reference
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Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia

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