Clinical trial NCT01475825: A Study of the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients With Familial Hypercholesterolemia and Inadequately Controlled Low-Density Lipoprotein Cholesterol
Official title: A Phase 3, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study Followed by an Open-Label Continuation Period to Assess the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients With Familial Hypercholesterolemia and Inadequately Controlled Low-Density Lipoprotein Cholesterol
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Hypercholesterolemia
Heterozygous Familial
Lead sponsor: Kastle Therapeutics, LLC
Sponsor class: INDUSTRY
First posted: 2011-11-21
Enrollment: 309
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Primary objective:

Determine whether mipomersen (ISIS 301012) significantly reduces atherogenic lipid levels in patients with severe heterozygous familial hypercholesterolemia (severe HeFH), defined as low-density lipoprotein cholesterol (LDL-C) levels ≥200 mg/dL plus the presence of coronary heart disease (CHD)/risk equivalents or LDL-C levels ≥300 mg/dL regardless of the presence of CHD/risk equivalents (referred to as Cohort 1) compared to placebo. Two different mipomersen dosing regimens will be studied: subcutaneous (SC) mipomersen 200 mg once weekly versus placebo, and SC mipomersen 70 mg thrice weekly versus placebo.

Secondary Objectives:

* Determine whether there are qualitative differences between the safety profiles of the 2 dosing regimens and placebo in Cohort 1, patients with HeFH with LDL-C levels ≥160 mg/dL and \<200 mg/dL plus the presence of CHD/risk equivalents (referred to as Cohort 2), and the overall study population
* Determine whether there are qualitative differences between the tolerability of the 2 dosing regimens and placebo in Cohort 1, Cohort 2, and the overall study population
* Further characterize the pharmacokinetics (PK) of the 2 dosing regimens in Cohort 1, Cohort 2, and the overall study population
* Determine whether the 2 mipomersen dosing regimens significantly reduce atherogenic lipid levels in Cohort 2 compared to placebo
* Obtain additional data regarding ongoing safety and efficacy of mipomersen in patients with FH and inadequately controlled LDL-C who complete the primary efficacy assessment visit (PET) in the Blinded Treatment Period and continue treatment in Open-Label Continuation Period

Detailed description: The study consisted of a Screening period of up to 4 weeks, Blinded Treatment Phase of 60 weeks, Open-Label Continuation Period of 26 weeks, and Post-Treatment Phase of 24 weeks.

Study Design, masking - Study treatment was blinded (double-blinded) through the Primary Efficacy Assessment Visit in the Blinded Treatment Period. Study treatment was open-label in the Open-Label Continuation Period.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of severe hypercholesterolemia (LDL-C ≥300 mg/dL (7.77 mmol/L) or LDL-C ≥200 mg/dL (5.18 mmol/L) with documented coronary heart disease (CHD) or CHD risk equivalents, or diagnosis of Heterozygous Familial Hypercholesterolemia and LDL-C ≥160 mg/dL (4.14 mmol/L) and \<200 mg/dL (5.18 mmol/L))
* On stable, maximally tolerated, statin therapy for at least 12 weeks or if statin intolerant, on at least 1 medication from another class of hypolipidemic agents (i.e., bile acid sequestrants, niacin/nicotinic acid, cholesterol absorption inhibitors, fibrates).
* On stable, low fat diet for 12 weeks
* Body mass index (BMI) ≤40 kg/m2 and stable weight for \> 6 weeks

Exclusion Criteria:

* Significant health problems in the recent past including heart attack, stroke, coronary syndrome, unstable angina, heart failure, significant arrhythmia, hypertension, blood disorders, liver disease, cancer, digestive disorders, Type I diabetes, or uncontrolled Type II diabetes
* Apheresis within 3 months prior to Screening or expected to start apheresis during the treatment phase

Primary outcomes:
measure: Percent Change From Baseline To Primary Endpoint Visit (PET) In LDL-C In Cohort 1
timeFrame: Baseline and Week 61
Secondary outcomes:
measure: Percent Change From Baseline To PET In LDL-C In Cohort 2
timeFrame: Baseline, PET (up to 60 weeks)
measure: Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 1
timeFrame: Baseline and Week 61
measure: Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 2
timeFrame: Baseline and Week 61
measure: Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 1
timeFrame: Baseline and Week 61
measure: Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 2
timeFrame: Baseline and Week 61
Other outcomes:
Locations:
city: Mission Viejo
country: United States
state: California
city: Aurora
country: United States
state: Colorado
city: Cooper City
country: United States
state: Florida
city: Winter Park
country: United States
state: Florida
city: Indianapolis
country: United States
state: Indiana
city: Kansas City
country: United States
state: Kansas
city: Boston
country: United States
state: Massachusetts
city: Ann Arbor
country: United States
state: Michigan
city: Grandville
country: United States
state: Michigan
city: Rochester
country: United States
state: Minnesota
city: Saint Louis
country: United States
state: Missouri
city: Omaha
country: United States
state: Nebraska
city: Summit
country: United States
state: New Jersey
city: North Massapequa
country: United States
state: New York
city: Portland
country: United States
state: Oregon
city: Lancaster
country: United States
state: Pennsylvania
city: Charleston
country: United States
state: South Carolina
city: Nashville
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Norfolk
country: United States
state: Virginia
city: Ciudad Autonoma de Buenos Aires
country: Argentina
city: Cordoba
country: Argentina
city: Perth
country: Australia
city: South Brisbane
country: Australia
city: Edegem
country: Belgium
city: Haine St. Paul
country: Belgium
city: Leuven
country: Belgium
city: Rio de Janeiro
country: Brazil
city: Sao Paulo
country: Brazil
city: Chicoutimi
country: Canada
state: Quebec
city: Montreal
country: Canada
state: Quebec
city: Sainte-Foy
country: Canada
state: Quebec
city: Osijek
country: Croatia
city: Zagreb
country: Croatia
city: Hradec Kralove
country: Czechia
city: Praha 1
country: Czechia
city: Aarhus
country: Denmark
city: Viborg
country: Denmark
city: Aachen
country: Germany
city: Berlin
country: Germany
city: Freiburg
country: Germany
city: Hamburg
country: Germany
city: Heidelberg
country: Germany
city: Koeln
country: Germany
city: Magdeburg
country: Germany
city: Ioannina
country: Greece
city: Kallithea
country: Greece
city: Hong Kong
country: Hong Kong
city: Baja
country: Hungary
city: Budapest
country: Hungary
city: Debrecen
country: Hungary
city: New Delhi
country: India
city: Holon
country: Israel
city: Kfar Saba
country: Israel
city: Ofakim
country: Israel
city: Bologna
country: Italy
city: Napoli
country: Italy
city: Padova
country: Italy
city: Palermo
country: Italy
city: Pisa
country: Italy
city: Roma
country: Italy
city: Seoul
country: Korea, Republic of
city: Kuala Lumpur
country: Malaysia
city: Kubang Kerian
country: Malaysia
city: Alkmaar
country: Netherlands
city: Amsterdam
country: Netherlands
city: Maastricht
country: Netherlands
city: Nijmegen
country: Netherlands
city: Utrecht
country: Netherlands
city: Waalwijk
country: Netherlands
city: Christchurch
country: New Zealand
city: Bodo
country: Norway
city: Oslo
country: Norway
city: Sandefjord
country: Norway
city: Bialystok
country: Poland
city: Gdansk
country: Poland
city: Katowice
country: Poland
city: Krakow
country: Poland
city: Naleczow
country: Poland
city: Poznan
country: Poland
city: Sopot
country: Poland
city: Szczecin
country: Poland
city: Warszawa
country: Poland
city: Wroclaw
country: Poland
city: Barnaul
country: Russian Federation
city: Kemerovo
country: Russian Federation
city: Moscow
country: Russian Federation
city: Novosibirsk
country: Russian Federation
city: Petrozavodsk
country: Russian Federation
city: Ryazan
country: Russian Federation
city: Saint Petersburg
country: Russian Federation
city: St-Petersburg
country: Russian Federation
city: St. Petersburg
country: Russian Federation
city: Tomsk
country: Russian Federation
city: Yaroslavl
country: Russian Federation
city: Cape Town
country: South Africa
city: Pretoria
country: South Africa
city: Madrid
country: Spain
city: Stockholm
country: Sweden
city: New Taipei City
country: Taiwan
city: Taipei
country: Taiwan
city: Ankara
country: Turkey
city: Istanbul
country: Turkey
city: Izmir
country: Turkey
city: Sivas
country: Turkey
city: Ivano-Frankivsk
country: Ukraine
city: Kiev
country: Ukraine
city: Kyiv
country: Ukraine
city: Odesa
country: Ukraine
city: Odessa
country: Ukraine
city: Birmingham
country: United Kingdom
city: Cardiff
country: United Kingdom
city: Liverpool
country: United Kingdom
city: London
country: United Kingdom
city: Manchester
country: United Kingdom
city: Oldham
country: United Kingdom
Study officials:
affiliation: Genzyme, a Sanofi Company
name: Medical Monitor
role: STUDY_DIRECTOR
References:
citation: Tragante V, Asselbergs FW, Swerdlow DI, Palmer TM, Moore JH, de Bakker PIW, Keating BJ, Holmes MV. Harnessing publicly available genetic data to prioritize lipid modifying therapeutic targets for prevention of coronary heart disease based on dysglycemic risk. Hum Genet. 2016 May;135(5):453-467. doi: 10.1007/s00439-016-1647-9. Epub 2016 Mar 5.