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

NCT ID: NCT00607373

Last Updated: 2016-09-09

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE3
• Total Enrollment: 51 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-07-31
• Study Completion Date: 2009-03-31

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.

Conditions

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

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

Mipomersen

Participants received mipomersen 200 mg as a subcutaneous injection once a week for 26 weeks.

Group Type: EXPERIMENTAL

mipomersen

Intervention Type: DRUG

200 mg mipomersen administered once a week for 26 weeks as a 1 mL subcutaneous injection. Subjects weighing less than 50 kg received a lower dose of 160 mg (0.8mL) mipomersen.

Placebo

Participants received placebo as a subcutaneous injection once a week for 26 weeks.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

1 mL subcutaneous injection once a week for 26 weeks. Subjects weighing less than 50 kg received 0.8 mL subcutaneous injection.

Interventions

mipomersen

200 mg mipomersen administered once a week for 26 weeks as a 1 mL subcutaneous injection. Subjects weighing less than 50 kg received a lower dose of 160 mg (0.8mL) mipomersen.

Intervention Type: DRUG

Placebo

1 mL subcutaneous injection once a week for 26 weeks. Subjects weighing less than 50 kg received 0.8 mL subcutaneous injection.

Intervention Type: DRUG

Other Intervention Names

ISIS 301012; mipomersen sodium; Kynamro™

Eligibility Criteria

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

• Minimum Eligible Age: 12 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Ionis Pharmaceuticals, Inc.

INDUSTRY

Sponsor Role: collaborator

Kastle Therapeutics, LLC

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Medical Monitor

Role: STUDY_DIRECTOR

Genzyme, a Sanofi Company

Locations

Charlotte, North Carolina, United States

Cincinnati, Ohio, United States

São Paulo, São Paulo, Brazil

Chicoutimi, Quebec, Canada

Ste Foy, Quebec, Canada

Mistri Wing, , Singapore

Observatory, , South Africa

Parktown, , South Africa

Taipei, , Taiwan

London, , United Kingdom

Countries

United States; Brazil; Canada; Singapore; South Africa; Taiwan; United Kingdom

References

Duell PB, Santos RD, Kirwan BA, Witztum JL, Tsimikas S, Kastelein JJP. Long-term mipomersen treatment is associated with a reduction in cardiovascular events in patients with familial hypercholesterolemia. J Clin Lipidol. 2016 Jul-Aug;10(4):1011-1021. doi: 10.1016/j.jacl.2016.04.013. Epub 2016 May 9.

Reference Type: DERIVED

PMID: 27578134 (View on PubMed)

Santos RD, Raal FJ, Catapano AL, Witztum JL, Steinhagen-Thiessen E, Tsimikas S. Mipomersen, an antisense oligonucleotide to apolipoprotein B-100, reduces lipoprotein(a) in various populations with hypercholesterolemia: results of 4 phase III trials. Arterioscler Thromb Vasc Biol. 2015 Mar;35(3):689-99. doi: 10.1161/ATVBAHA.114.304549. Epub 2015 Jan 22.

Reference Type: DERIVED

PMID: 25614280 (View on PubMed)

Raal FJ, Santos RD, Blom DJ, Marais AD, Charng MJ, Cromwell WC, Lachmann RH, Gaudet D, Tan JL, Chasan-Taber S, Tribble DL, Flaim JD, Crooke ST. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010 Mar 20;375(9719):998-1006. doi: 10.1016/S0140-6736(10)60284-X.

Reference Type: DERIVED

PMID: 20227758 (View on PubMed)

Other Identifiers

2005-003449-15

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

301012CS5

Identifier Type: -

Identifier Source: org_study_id