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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 (FOCUS FH)

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ClinicalTrials.gov Identifier: NCT01475825
Recruitment Status : Completed
First Posted : November 21, 2011
Results First Posted : March 14, 2019
Last Update Posted : March 26, 2019
Sponsor:
Information provided by (Responsible Party):
Kastle Therapeutics, LLC

Tracking Information
First Submitted Date  ICMJE November 17, 2011
First Posted Date  ICMJE November 21, 2011
Results First Submitted Date  ICMJE November 13, 2018
Results First Posted Date  ICMJE March 14, 2019
Last Update Posted Date March 26, 2019
Actual Study Start Date  ICMJE December 2011
Actual Primary Completion Date December 29, 2015   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 26, 2019)
Percent Change From Baseline To Primary Endpoint Visit (PET) In LDL-C In Cohort 1 [ Time Frame: Baseline and Week 61 ]
The percent change from baseline to PET in LDL-C was measured in Cohort 1, which included participants with severe heterozygous familial hypercholesterolemia (HeFH). Severe HeFH was defined as LDL-C levels ≥200 mg/deciliter (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.
Original Primary Outcome Measures  ICMJE
 (submitted: November 17, 2011)
Percent change from Baseline in low-density lipoprotein cholesterol (LDL-C) in Cohort 1 [ Time Frame: Baseline and Week 60 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 26, 2019)
  • Percent Change From Baseline To PET In LDL-C In Cohort 2 [ Time Frame: Baseline, PET (up to 60 weeks) ]
    The percent change from baseline to PET in LDL-C was measured in Cohort 2, which included participants with HeFH with LDL-C levels ≥160 mg/dL and <200 mg/dL, plus the presence of CHD/risk equivalents.
  • Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 1 [ Time Frame: Baseline and Week 61 ]
    The percent change from baseline to PET in Apo B was measured in participants in Cohort 1 with HeFH during the Blinded Treatment Period.
  • Percent Change From Baseline To PET In Apolipoprotein B (Apo B) In Cohort 2 [ Time Frame: Baseline and Week 61 ]
    The percent change from baseline to PET in Apo B was measured in participants in Cohort 2 with HeFH during the Blinded Treatment Period.
  • Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 1 [ Time Frame: Baseline and Week 61 ]
    The percent change from baseline to PET in Lipoprotein A1 was measured in participants in Cohort 1 with HeFH during the Blinded Treatment Period.
  • Percent Change From Baseline To PET in Lipoprotein (a) In Cohort 2 [ Time Frame: Baseline and Week 61 ]
    The percent change from baseline to PET in Lipoprotein A1 was measured in participants in Cohort 2 with HeFH during the Blinded Treatment Period.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 17, 2011)
  • Percent Change from Baseline in Apolipoprotein B (Apo B) [ Time Frame: Baseline and Week 60 ]
  • Percent Change from Baseline in Lipoprotein a [ Time Frame: Baseline and Week 60 ]
  • Percent Change from Baseline in LDL-C in Cohort 2 [ Time Frame: Baseline and Week 60 ]
  • Number of Participants with Adverse Events [ Time Frame: 60 weeks ]
  • Number of Participants with Injection Site Reactions [ Time Frame: 60 weeks ]
  • Blood plasma concentration of Mipomersen [ Time Frame: Pre-dose and at 2, 4, 6, 24, 48 and 72 hours post-dose at Weeks 1, 30, 36 and 60. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE 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  ICMJE 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
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Hypercholesterolemia
  • Heterozygous Familial
Intervention  ICMJE
  • Drug: mipomersen sodium 200 mg
    Subcutaneous mipomersen 200 mg once weekly
    Other Name: Kynamro (ISIS 301012)
  • Drug: Placebo
    Placebo vehicle for subcutaneous injection.
  • Drug: mipomersen sodium 70 mg
    Subcutaneous mipomersen 70 mg thrice weekly
    Other Name: Kynamro (ISIS 301012)
Study Arms  ICMJE
  • Experimental: Regimen A: Mipomersen
    Subcutaneous injection of mipomersen 200 mg once weekly
    Intervention: Drug: mipomersen sodium 200 mg
  • Placebo Comparator: Regimen A: Placebo
    Placebo matching subcutaneous injection once weekly.
    Intervention: Drug: Placebo
  • Experimental: Regimen B: Mipomersen
    Subcutaneous injection of mipomersen 70 mg thrice weekly.
    Intervention: Drug: mipomersen sodium 70 mg
  • Placebo Comparator: Regimen B: Placebo
    Placebo matching subcutaneous injection thrice weekly.
    Intervention: Drug: Placebo
Publications * 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.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: February 26, 2019)
309
Original Estimated Enrollment  ICMJE
 (submitted: November 17, 2011)
480
Actual Study Completion Date  ICMJE December 29, 2015
Actual Primary Completion Date December 29, 2015   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Argentina,   Australia,   Belgium,   Brazil,   Canada,   Croatia,   Czechia,   Denmark,   Germany,   Greece,   Hong Kong,   Hungary,   India,   Israel,   Italy,   Korea, Republic of,   Malaysia,   Netherlands,   New Zealand,   Norway,   Poland,   Russian Federation,   South Africa,   Spain,   Sweden,   Taiwan,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries Czech Republic
 
Administrative Information
NCT Number  ICMJE NCT01475825
Other Study ID Numbers  ICMJE MIPO3801011
2011-001480-42 ( EudraCT Number )
EFC12875 ( Other Identifier: Sanofi )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Kastle Therapeutics, LLC
Study Sponsor  ICMJE Kastle Therapeutics, LLC
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Monitor Genzyme, a Sanofi Company
PRS Account Kastle Therapeutics, LLC
Verification Date March 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP