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

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

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.

Study Overview

• Status: Completed
• Conditions: Metabolic Diseases; Congenital Abnormalities; Infant, Newborn, Diseases; Genetic Diseases, Inborn; Dyslipidemias; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hypercholesterolemia; Hyperlipidemias; Hyperlipoproteinemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemia Type II; Metabolic Disorder; Hypercholesterolemia, Autosomal Dominant
• Intervention / Treatment: Drug: Mipomersen Sodium

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 Type: Interventional
• Enrollment (Actual): 144
• Phase: Phase 3

Contacts and Locations

Study Locations

• Brazil
  • Sao Paulo, Brazil
• Canada
  • Quebec, Canada, G1V 4M6
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3A 1M5
  • Ontario
    • London, Ontario, Canada, N6A 5K8
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 5H6
    • Montreal, Quebec, Canada, H1T 1C8
    • Montreal, Quebec, Canada, H2W 1R7
    • Sherbrooke, Quebec, Canada, J1H 5N4
• 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
• United States
  • California
    • Mission Viejo, California, United States, 92691
    • Newport Beach, California, United States, 92660
  • Connecticut
    • Bridgeport, Connecticut, United States, 06606
  • Florida
    • Melbourne, Florida, United States, 32901
    • Winter Park, Florida, United States, 32792
  • Illinois
    • Chicago, Illinois, United States, 60654
  • Kansas
    • Kansas City, Kansas, United States, 66160
  • Maine
    • Biddeford, Maine, United States, 04005
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
  • Missouri
    • St Louis, Missouri, United States, 63110
  • New Hampshire
    • Concord, New Hampshire, United States, 03301
  • New York
    • New York, New York, United States, 10032
  • North Carolina
    • Charlotte, North Carolina, United States, 28204
    • Durham, North Carolina, United States, 27710
  • Ohio
    • Cincinnati, Ohio, United States, 45212
    • Franklin, Ohio, United States, 45005
  • Oregon
    • Portland, Oregon, United States, 97239
  • Tennessee
    • Nashville, Tennessee, United States, 37232
  • Texas
    • Dallas, Texas, United States, 75226
  • Washington
    • Seattle, Washington, United States, 98104

Participation Criteria

Eligibility Criteria

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

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C)	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).	Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in Apolipoprotein B (Apo B)	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).	Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in Total Cholesterol	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).	Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in Non High Density Lipoprotein Cholesterol (Non-HDL-C)	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).	Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Triglycerides	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).	Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in Lipoprotein (a)	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).	Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in LDL Particles' Size (Total)	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in LDL Particles' Size (Large)	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in LDL Particles' Size (Medium)	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in LDL Particles' Size (Small)	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in LDL Particles' Size (Very Small)	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in HDL Particles' Size (Large)	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in HDL Particles' Size (Medium)	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in HDL Particles' Size (Small)	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in Intermediate Density Lipoprotein Particles' Size	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in Very Low Density Lipoprotein (VLDL) Particles' Size (Large) and Chylomicron Particles' Size	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in VLDL Particles' Size (Medium)	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in VLDL Particles' Size (Small)	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in Total VLDL Particles' Size and Chylomicron Particles' Size	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Change From Baseline in C-Reactive Protein	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).	Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
Percent Change From Baseline in Apolipoprotein A-1	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).	Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)

Collaborators and Investigators

• Sponsor: Kastle Therapeutics, LLC
• Collaborators: Ionis Pharmaceuticals, Inc.

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: June 5, 2008
• First Submitted That Met QC Criteria: June 5, 2008
• First Posted (Estimate): June 10, 2008

Study Record Updates

• Last Update Posted (Estimate): September 9, 2016
• Last Update Submitted That Met QC Criteria: August 1, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: FH; Heterozygous Familial Hypercholesterolemia; HeFH; Familial Hypercholesterolemia; Homozygous Familial Hypercholesterolemia; HoFH
• Additional Relevant MeSH Terms: Pathologic Processes; Disease; Dyslipidemias; Congenital Abnormalities; Hypercholesterolemia; Hyperlipidemias; Metabolism, Inborn Errors; Metabolic Diseases; Hyperlipoproteinemia Type II; Lipid Metabolism Disorders; Genetic Diseases, Inborn; Infant, Newborn, Diseases; Hyperlipoproteinemias; Lipid Metabolism, Inborn Errors; Molecular Mechanisms of Pharmacological Action; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Mipomersen
• Other Study ID Numbers: 301012-CS6; 2005-003450-10 (EudraCT Number)