An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia

• ClinicalTrials.gov Identifier: NCT00694109
• Recruitment Status: Completed
• First Posted: June 10, 2008
• Results First Posted: December 21, 2015
• Last Update Posted: September 9, 2016
• Sponsor: Kastle Therapeutics, LLC
• Collaborator: Ionis Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Kastle Therapeutics, LLC

Study Description

Brief Summary:

To evaluate the safety and efficacy of extended dosing with mipomersen (ISIS 301012) in participants with familial hypercholesterolemia or severe hypercholesterolemia on lipid-lowering therapy who had completed either the 301012-CS5 (NCT00607373), 301012-CS7 (NCT00706849), 301012-CS17 (NCT00477594) or MIPO3500108 (NCT00794664) clinical drug trials.

Condition or disease	Intervention/treatment	Phase
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	Drug: Mipomersen Sodium	Phase 3

Detailed Description:

All familial hypercholesterolemia (FH) or severe hypercholesterolemia participants who had tolerated the treatment regimen in Protocol 301012-CS5 (NCT00607373), 301012-CS7 (NCT00706849) or MIPO3500108 (NCT00794664) and satisfactorily completed the study through to Week 28 were eligible for participation in this open label treatment extension study for up to 4 years or until mipomersen was commercially available, whichever comes first. Consenting participants who had tolerated mipomersen and satisfactorily completed 301012-CS17 (NCT00477594) through Year 3 may also enroll for up to an additional 2 years of treatment in this study or until mipomersen was commercially available, whichever comes first. All participants, who entered the study, received 200 mg mipomersen (ISIS 301012) subcutaneously (s.c.) every week, including those who were randomized to placebo in their initial study. Participants who were originally enrolled in Protocol 301012-CS5 (NCT00607373) and weighed <50 kg received 160 mg every week. Dose adjustments (70 mg injections administered three times per week, on separate days) were allowed for participants who were not tolerating or who had previous issues with tolerating the once a week injections due to injection site reactions (ISRs) or flu-like symptoms. Study visits and clinical lab assessments including hematology with differential, chemistry, serum lipid panel (total cholesterol, LDL-C, very low density lipoprotein cholesterol (VLDL-C), high density lipoprotein cholesterol (HDL-C), apolipoprotein B (apoB), apoA-1, triglycerides (TG) and Lp(a), and urinalysis was to be performed every 4-10 weeks during the treatment period. Plasma trough mipomersen (ISIS 301012) levels was to be measured to estimate exposure. Participants who completed dosing or who discontinued prematurely from the study for any reason was followed for safety for 24 weeks (safety follow-up period) after their last dose of mipomersen (ISIS 301012) or longer in the case of a significant adverse events (AE) or abnormal biochemical or clinical finding. Participants were required to return to the study center for clinical evaluation and clinical laboratory tests every 8 weeks during the safety follow-up period.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 144 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia
• Study Start Date: April 2008
• Actual Primary Completion Date: September 2014
• Actual Study Completion Date: September 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Mipomersen; Mipomersen Sodium once a week for up to 4 years (depending on participant's consent). Participants were followed for additional 24 week post-treatment.	Drug: Mipomersen Sodium; Subcutaneous injection as a single injection directly into the abdomen, thigh, or outer area of the upper arm.; Other Names: ISIS 301012; Kynamro®

Outcome Measures

Primary Outcome Measures :

1. Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C) [ Time Frame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
2. Percent Change From Baseline in Apolipoprotein B (Apo B) [ Time Frame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
3. Percent Change From Baseline in Total Cholesterol [ Time Frame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
4. Percent Change From Baseline in Non High Density Lipoprotein Cholesterol (Non-HDL-C) [ Time Frame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).

Secondary Outcome Measures :

1. Percent Change From Baseline in Triglycerides [ Time Frame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
2. Percent Change From Baseline in Lipoprotein (a) [ Time Frame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
3. Percent Change From Baseline in LDL Particles' Size (Total) [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
4. Percent Change From Baseline in LDL Particles' Size (Large) [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
5. Percent Change From Baseline in LDL Particles' Size (Medium) [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
6. Percent Change From Baseline in LDL Particles' Size (Small) [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
7. Percent Change From Baseline in LDL Particles' Size (Very Small) [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
8. Percent Change From Baseline in HDL Particles' Size (Large) [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
9. Percent Change From Baseline in HDL Particles' Size (Medium) [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
   Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
10. Percent Change From Baseline in HDL Particles' Size (Small) [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
11. Percent Change From Baseline in Intermediate Density Lipoprotein Particles' Size [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
12. Percent Change From Baseline in Very Low Density Lipoprotein (VLDL) Particles' Size (Large) and Chylomicron Particles' Size [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
13. Percent Change From Baseline in VLDL Particles' Size (Medium) [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
14. Percent Change From Baseline in VLDL Particles' Size (Small) [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
15. Percent Change From Baseline in Total VLDL Particles' Size and Chylomicron Particles' Size [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
16. Change From Baseline in C-Reactive Protein [ Time Frame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years) ]
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).
17. Percent Change From Baseline in Apolipoprotein A-1 [ Time Frame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years) ]
    Baseline was defined as the last value prior to receiving the first dose of mipomersen in this study (for participants randomized to placebo in their index study and for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered >=6 months from their last dose of mipomersen in their index study), or the last value prior to receiving the first dose of mipomersen in their index study (for participants randomized to mipomersen in their index study and their first dose of mipomersen in this study was administered <6 months from their last dose of mipomersen in their index study).

Eligibility Criteria

• Ages Eligible for Study: 12 Years and older (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Satisfactory completion of dosing in their initial study (Protocol 301012-CS5 [NCT00607373], 301012-CS7 [NCT00706849], 301012-CS17 [NCT00477594], or MIPO3500108 [NCT00794664])

Exclusion Criteria:

• Had any new condition or worsening of existing condition which in the opinion of the Investigator would make the participant unsuitable for enrollment, or could interfere with the participant participating in or completing the study

Contacts and Locations

Locations

United States, California

Mission Viejo, California, United States, 92691

Newport Beach, California, United States, 92660

United States, Connecticut

Bridgeport, Connecticut, United States, 06606

United States, Florida

Melbourne, Florida, United States, 32901

Winter Park, Florida, United States, 32792

United States, Illinois

Chicago, Illinois, United States, 60654

United States, Kansas

Kansas City, Kansas, United States, 66160

United States, Maine

Biddeford, Maine, United States, 04005

United States, Massachusetts

Boston, Massachusetts, United States, 02114

United States, Missouri

St Louis, Missouri, United States, 63110

United States, New Hampshire

Concord, New Hampshire, United States, 03301

United States, New York

New York, New York, United States, 10032

United States, North Carolina

Charlotte, North Carolina, United States, 28204

Durham, North Carolina, United States, 27710

United States, Ohio

Cincinnati, Ohio, United States, 45212

Franklin, Ohio, United States, 45005

United States, Oregon

Portland, Oregon, United States, 97239

United States, Tennessee

Nashville, Tennessee, United States, 37232

United States, Texas

Dallas, Texas, United States, 75226

United States, Washington

Seattle, Washington, United States, 98104

Brazil

Sao Paulo, Brazil

Canada, Manitoba

Winnipeg, Manitoba, Canada, R3A 1M5

Canada, Ontario

London, Ontario, Canada, N6A 5K8

Canada, Quebec

Chicoutimi, Quebec, Canada, G7H 5H6

Montreal, Quebec, Canada, H1T 1C8

Montreal, Quebec, Canada, H2W 1R7

Sherbrooke, Quebec, Canada, J1H 5N4

Canada

Quebec, Canada, G1V 4M6

Singapore

Singapore, Singapore, 168752

South Africa

Observatory, South Africa, 7925

Parktown, South Africa, 2193

Taiwan

Taipei, Taiwan, 11217

United Kingdom

London, United Kingdom, WC1N 3BG

Sponsors and Collaborators

Kastle Therapeutics, LLC

Ionis Pharmaceuticals, Inc.

Investigators

• Study Director: Medical Monitor; Genzyme, a Sanofi Company

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Santos RD, Duell PB, East C, Guyton JR, Moriarty PM, Chin W, Mittleman RS. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J. 2015 Mar 1;36(9):566-75. doi: 10.1093/eurheartj/eht549. Epub 2013 Dec 23.

• Responsible Party: Kastle Therapeutics, LLC
• ClinicalTrials.gov Identifier: NCT00694109
• Other Study ID Numbers: 301012-CS6; 2005-003450-10 ( EudraCT Number )
• First Posted: June 10, 2008
• Results First Posted: December 21, 2015
• Last Update Posted: September 9, 2016
• Last Verified: August 2016

Keywords provided by Kastle Therapeutics, LLC:

Familial Hypercholesterolemia; FH; Heterozygous Familial Hypercholesterolemia; HeFH; Homozygous Familial Hypercholesterolemia; HoFH

Additional relevant MeSH terms:

Congenital Abnormalities; Hyperlipoproteinemia Type II; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Infant, Newborn, Diseases; Lipid Metabolism, Inborn Errors; Hypercholesterolemia; Dyslipidemias; Hyperlipidemias; Hyperlipoproteinemias; Metabolic Diseases; Lipid Metabolism Disorders; Disease; Pathologic Processes; Mipomersen; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents