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

NCT00607373 | Completed Phase 3 Results DMC

• 2 other identifiers: 301012CS52005-003449-15
• Study Type: interventional
• Target: 51
• Locations: 7 countries
• Sites: 10

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.

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

Keywords

Apolipoprotein B; Homozygous Familial Hypercholesterolemia; LDL-receptor gene

Outcome Measures

Primary Outcomes (2)

• Percent Change From Baseline in Low-density Lipoprotein Cholesterol (LDL-C) at Primary Efficacy Time Point

  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.

  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 at Baseline and the Primary Efficacy Time Point (PET)

  The PET was the post-baseline visit, for which LDL-C was assessed, closest to 14 days after the last dose of study drug.

  Baseline (the average of the screening and Day 1 pre-treatment assessments) and the Primary Efficacy Time point (PET) up to week 28

Secondary Outcomes (6)

• 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 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 )

• 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 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

• 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

Other Outcomes (12)

• Percentage Change From Baseline in Triglycerides 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

• Triglycerides 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

• Percentage Change From Baseline in Lipoprotein(a) 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

Study Arms (2)

Mipomersen

EXPERIMENTAL

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

Drug: mipomersen

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

mipomersen 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.

Also known as: ISIS 301012, mipomersen sodium, Kynamro™

Mipomersen

Placebo DRUG

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

Placebo

Eligibility Criteria

• Age: 12 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• Kastle Therapeutics, LLC: lead
• Ionis Pharmaceuticals, Inc.: collaborator

Study Sites (10)

Unknown Facility

Charlotte, North Carolina, 28204, United States

Location

Unknown Facility

Cincinnati, Ohio, 45212, United States

Location

Unknown Facility

São Paulo, São Paulo, 05403-000, Brazil

Location

Unknown Facility

Chicoutimi, Quebec, G7H 5H6, Canada

Location

Unknown Facility

Ste Foy, Quebec, G1V 4G2, Canada

Location

Unknown Facility

Mistri Wing, 168752, Singapore

Location

Unknown Facility

Observatory, 7925, South Africa

Location

Unknown Facility

Parktown, 2193, South Africa

Location

Unknown Facility

Taipei, 11217, Taiwan

Location

Unknown Facility

London, WC1N 3BG, United Kingdom

Location

Related Publications (3)

• 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.

  PMID: 27578134 DERIVED

• 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.

  PMID: 25614280 DERIVED

• 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.

  PMID: 20227758 DERIVED

MeSH Terms

Conditions

Lipid Metabolism, Inborn Errors; Hyperlipoproteinemia Type II; Hyperlipidemias; Metabolic Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Congenital Abnormalities; Hypercholesterolemia; Hyperlipoproteinemias; Dyslipidemias; Lipid Metabolism Disorders; Homozygous Familial Hypercholesterolemia

Interventions

mipomersen

Condition Hierarchy (Ancestors)

Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases

Results Point of Contact

• Title: Genzyme Medical Information
• Organization: Genzyme Corporation

617-252-7832

Study Officials

• Medical Monitor

  Genzyme, a Sanofi Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 22, 2008
• First Posted: February 5, 2008
• Study Start: July 1, 2007
• Primary Completion: March 1, 2009
• Study Completion: March 1, 2009
• Last Updated: September 9, 2016
• Results First Posted: March 21, 2013

Record last verified: 2016-08

Locations

TW (1); GB (1); US (2); ZA (2); BR (1); CA (2); SG (1)