Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial Hypercholesterolemia

Phase 3

Completed

• Conditions: Metabolic Diseases; Hypercholesterolemia; Hyperlipidemias; Metabolism, Inborn Errors; Metabolic Disorder; Hyperlipoproteinemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Genetic Diseases, Inborn; Infant, Newborn, Diseases
• Interventions: Drug: Placebo; Drug: mipomersen

• Registration Number: NCT00607373
• Lead Sponsor: Kastle Therapeutics, LLC

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of mipomersen (ISIS 301012) in subjects with homozygous familial hypercholesterolemia on lipid-lowering therapy.

This study consisted of a 26-week treatment period and a 24-week post-treatment follow-up period. Following treatment and Week 28 evaluations, participants could elect to enroll in an open-label extension study (301012-CS6; NCT00694109). Participants who were not eligible or elected not to enroll in the open-label extension study or who discontinued during the 28-week treatment period were followed in this study for 24 weeks from administration of the last dose of study drug.

Detailed Description

Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder of lipoprotein metabolism characterized by markedly elevated low density lipoprotein (LDL), premature onset of atherosclerosis and development of xanthomata. Patients with homozygous familial hypercholesterolemia (HoFH) have a severe disease that presents in childhood with total cholesterol typically in the 650 to 1000 mg/dL range.

This was a randomized, double-blind, placebo-controlled study, which consisted of a 4-week screening period, 26 weeks of treatment, and a 24-week post- treatment follow-up period (with the exception of patients who enrolled in the open-label extension study, Study 301012-CS6; NCT00694109). Eligible patients were randomized in a 2:1 ratio to receive 200 mg mipomersen or matching volume placebo subcutaneous (SC) injections weekly. Patients who weighed \<50 kg received a lower dose of 160 mg mipomersen or matching volume of placebo SC injections weekly. Patients were to have been on a stable (\>=12 weeks) regimen of allowed lipid-lowering therapies at screening, and were required to remain on the same dose and regimen throughout the study.

Patients returned to the study center for clinical evaluation every other week during the first 4 weeks of treatment, once every 4 to 5 weeks for the remainder of the treatment period, and monthly during the post-treatment evaluation (follow-up) period. The primary endpoint assessment was at Week 28. Following treatment and Week 28 evaluations, eligible patients who tolerated the study drug could elect to enroll in the open-label extension study (Study 301012-CS6; NCT00694109). Patients who did not participate in the open-label extension study were required to return to the study center for clinical evaluation at least twice during the post-treatment follow-up period, including an end-of-study termination visit at the end of this 24-week period.

Study Timeline

• Study Start: 2007-07
• Study First Submitted: 2008-01-22
• Study First Submitted QC: 2008-02-04
• Study First Posted: 2008-02-05
• Primary Completion: 2009-03
• Study Completion: 2009-03
• Disposition First Submitted: 2010-10-02
• Disposition First Submitted QC: 2010-10-02
• Disposition First Posted: 2010-10-05
• Results First Submitted: 2013-02-15
• Results First Submitted QC: 2013-02-15
• Results First Posted: 2013-03-21
• Status Verified: 2016-08
• Last Update Submitted: 2016-08-01
• Last Update Posted: 2016-09-09

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 51

Inclusion Criteria

• Diagnosis of Homozygous Familial Hypercholesterolemia (HoFH)
• Stable lipid-lowering therapy for 12 weeks
• Stable weight for 6 weeks
• Stable low fat diet for 8 weeks

Exclusion Criteria

• Significant health problems in the recent past including heart attack, stroke, blood disorders, cancer, or digestive problems

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Participants received placebo as a subcutaneous injection once a week for 26 weeks.
Mipomersen	mipomersen	Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.

Primary Outcome Measures

Name	Time	Method
LDL-C at Baseline and the Primary Efficacy Time Point (PET)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	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. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. If the Study Day 1 and screening LDL-C values were \>12% different (relative to the maximum value), then the screening value was not used, because the Study Day 1 value represents the best estimate of the patient's condition at the beginning of study drug administration. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

Secondary Outcome Measures

Name	Time	Method
Non-HDL-C at Baseline and the Primary Efficacy Time Point (PET)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Percent Change From Baseline in Apolipoprotein B (Apo-B) at Primary Efficacy Time Point	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	Apo-B was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Apo-B at Baseline and the Primary Efficacy Time Point (PET)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28 )	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Percentage Change From Baseline in Total Cholesterol at Primary Efficacy Time Point (PET)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	Total cholesterol was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Total Cholesterol at Baseline and the Primary Efficacy Time Point (PET)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.
Percentage Change From Baseline in Non-High-Density Lipoprotein Cholesterol (Non-HDL-C) at Primary Efficacy Time Point (PET)	Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28	Non-HDL-C was measured in mg/dL. Samples were taken following an overnight fast. Baseline was defined as the average of the screening and Study Day 1 (pre-treatment) assessments. An assessment was not included in this calculation if it was associated with a non-fasting blood draw or was drawn more than 4 weeks prior to Study Day 1. The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.