Clinical trial NCT00694109: 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
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
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: Familial Hypercholesterolemia
FH
Heterozygous Familial Hypercholesterolemia
HeFH
Homozygous Familial Hypercholesterolemia
HoFH
Lead sponsor: Kastle Therapeutics, LLC
Sponsor class: INDUSTRY
Collaborators: name: Ionis Pharmaceuticals, Inc.
First posted: 2008-06-10
Enrollment: 144
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Percent Change From Baseline in Low Density Lipoprotein Cholesterol (LDL-C)
timeFrame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in Apolipoprotein B (Apo B)
timeFrame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in Total Cholesterol
timeFrame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in Non High Density Lipoprotein Cholesterol (Non-HDL-C)
timeFrame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
Secondary outcomes:
measure: Percent Change From Baseline in Triglycerides
timeFrame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in Lipoprotein (a)
timeFrame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in LDL Particles' Size (Total)
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in LDL Particles' Size (Large)
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in LDL Particles' Size (Medium)
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in LDL Particles' Size (Small)
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in LDL Particles' Size (Very Small)
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in HDL Particles' Size (Large)
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in HDL Particles' Size (Medium)
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in HDL Particles' Size (Small)
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in Intermediate Density Lipoprotein Particles' Size
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in Very Low Density Lipoprotein (VLDL) Particles' Size (Large) and Chylomicron Particles' Size
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in VLDL Particles' Size (Medium)
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in VLDL Particles' Size (Small)
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in Total VLDL Particles' Size and Chylomicron Particles' Size
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Change From Baseline in C-Reactive Protein
timeFrame: Baseline up to End of treatment; 24 weeks post treatment (up to 4.5 years)
measure: Percent Change From Baseline in Apolipoprotein A-1
timeFrame: Baseline up to Week 234; 24 weeks post treatment (up to 4.5 years)
Other outcomes:
Locations:
city: Mission Viejo
country: United States
state: California
city: Newport Beach
country: United States
state: California
city: Bridgeport
country: United States
state: Connecticut
city: Melbourne
country: United States
state: Florida
city: Winter Park
country: United States
state: Florida
city: Chicago
country: United States
state: Illinois
city: Kansas City
country: United States
state: Kansas
city: Biddeford
country: United States
state: Maine
city: Boston
country: United States
state: Massachusetts
city: St Louis
country: United States
state: Missouri
city: Concord
country: United States
state: New Hampshire
city: New York
country: United States
state: New York
city: Charlotte
country: United States
state: North Carolina
city: Durham
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Franklin
country: United States
state: Ohio
city: Portland
country: United States
state: Oregon
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Seattle
country: United States
state: Washington
city: Sao Paulo
country: Brazil
city: Winnipeg
country: Canada
state: Manitoba
city: London
country: Canada
state: Ontario
city: Chicoutimi
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Sherbrooke
country: Canada
state: Quebec
city: Quebec
country: Canada
city: Singapore
country: Singapore
city: Observatory
country: South Africa
city: Parktown
country: South Africa
city: Taipei
country: Taiwan
city: London
country: United Kingdom
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.