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

Hypercholesterolemia Clinical Trial

Official title:

An Open-Label Extension Study to Assess the Long-term Safety and Efficacy of Mipomersen in Subjects With Familial Hypercholesterolemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00477594
• Other study ID #: 301012-CS17
• Secondary ID: 2007-001024-12
• Status: Completed
• Phase: Phase 2
• First received: May 22, 2007
• Last updated: December 2, 2013
• Start date: May 2007
• Est. completion date: July 2011

Study information

• Verified date: December 2013
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 21
• Est. completion date: July 2011
• Est. primary completion date: March 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 12 Years and older

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Congenital Abnormalities
• Disease
• Dyslipidemias
• Genetic Diseases, Inborn
• Hypercholesterolemia
• Hypercholesterolemia, Autosomal Dominant
• Hyperlipidemias
• Hyperlipoproteinemia Type II
• Hyperlipoproteinemias
• Infant, Newborn, Diseases
• Lipid Metabolism Disorders
• Lipid Metabolism, Inborn Errors
• Metabolic Diseases
• Metabolic Disorder
• Metabolism, Inborn Errors

Intervention

Drug:
• mipomersen sodium
200 mg/ml, in 1 ml solution for subcutaneous injection.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Genzyme, a Sanofi Company	Ionis Pharmaceuticals, Inc.

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percent Change From Baseline in Triglycerides	Triglycerides were measured in mg/dL. Samples were taken following an overnight fast.	Baseline and Weeks 52 and 104.	No
Other	Triglycerides 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.	Baseline and Weeks 52 and 104.	No
Other	Percent Change From Baseline in Lipoprotein(a)	Lipoprotein(a) was measured in mg/dL. Samples were taken following an overnight fast.	Baseline and Weeks 52 and 104.	No
Other	Lipoprotein(a) 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.	Baseline and Weeks 52 and 104.	No
Other	Percent Change From Baseline in Very-Low-Density Lipoprotein (VLDL) Cholesterol	Very-Low-Density Lipoprotein (VLDL) Cholesterol was measured in mg/dL. Samples were taken following an overnight fast.	Baseline and Weeks 52 and 104.	No
Other	Very-Low-Density Lipoprotein (VLDL) 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.	Baseline and Weeks 52 and 104.	No
Other	Percent Change From Baseline in Ratio of Low-density Lipoprotein Cholesterol to High-density Lipoprotein Cholesterol		Baseline and Weeks 52 and 104.	No
Other	Ratio of Low-density Lipoprotein Cholesterol to 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.	Baseline and Weeks 52 and 104.	No
Other	Percent Change From Baseline in Apolipoprotein A1	Apolipoprotein A1 was measured in mg/dL. Samples were taken following an overnight fast.	Baseline and Weeks 52 and 104.	No
Other	Apolipoprotein A1 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.	Baseline and Weeks 52 and 104.	No
Other	Percent Change From Baseline in High-Density Lipoprotein Cholesterol	High-Density Lipoprotein (HDL) Cholesterol was measured in mg/dL. Samples were taken following an overnight fast.	Baseline and Weeks 52 and 104.	No
Other	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.	Baseline and Weeks 52 and 104.	No
Primary	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.	Baseline and Weeks 52 and 104	No
Primary	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.	Baseline and Weeks 52 and 104.	No
Secondary	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.	Baseline and Weeks 52 and 104	No
Secondary	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.	Baseline and Weeks 52 and 104.	No
Secondary	Percent Change From Baseline in Total Cholesterol	Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast.	Baseline and Weeks 52 and 104.	No
Secondary	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.	Baseline and Weeks 52 and 104.	No
Secondary	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.	Baseline and Weeks 52 and 104.	No
Secondary	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.	Baseline and Weeks 52 and 104.	No
Secondary	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.	2 years	Yes
Secondary	Percent Change From Baseline in Clinical Chemistry Parameters		Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.	Yes
Secondary	Percent Change From Baseline in Hematology Parameters		Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment	Yes
Secondary	Percent Change From Baseline in Blood Pressure		Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.	Yes
Secondary	Percent Change From Baseline in Pulse Rate		Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.	Yes
Secondary	Percent Change From Baseline in Respiratory Rate		Baseline and Week 104 or the Early Termination visit for participants who did not complete 2 years of treatment.	Yes