A Registration Study for Familial Hypercholesterolemia in Taiwan

Familial hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism, transmitted in an autosomal dominant manner and clinically characterized by elevated levels of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol, the presence of tendon xanthomas, and premature atherosclerosis.

The homozygous form of familial hypercholesterolemia (HoFH) with autosomal dominant transmission, in which case both alleles of either LDLR, APOB, or PCSK9 gene are defective, is a rare genetic disorder with prevalence estimated to be one per million population.

Large scale genetic screening for active FH cases finding has been performed in the Netherlands, Spain, Norway and Wales. However, the FH population and prevalence in Taiwan have never been formally studied. Patients are usually not under appropriate treatment owing to lack of standardized diagnostic tool and treatment strategy for FH. Moreover, with the emerging of new classes of LLTs, including microsomal triglyceride transfer protein (MTP) inhibitor, antisense oligonucleotide inhibitor, and PCSK9 inhibitors, even homozygous FH patients now have better chance to be treated to reach recommended treatment goals. Therefore, A National FH registry is needed to collect contemporary data on diagnosis, treatment and outcomes with long- term goals of improving diagnosis, management, and reduction of unnecessary cardiovascular events in FH population in Taiwan.

Study Overview

• Status: Unknown
• Conditions: Familial Hypercholesterolemia

Detailed Description

Familial hypercholesterolemia (FH) is an inherited disorder of lipoprotein metabolism, transmitted in an autosomal dominant manner and clinically characterized by elevated levels of total cholesterol (TC) and low-density lipoprotein (LDL) cholesterol, the presence of tendon xanthomas, and premature atherosclerosis.The genetic basis of FH is a large array of point mutations and large gene rearrangements in the LDL receptor (LDLR) gene, resulting in defective functional receptors for LDL on the cell surface, which are unable to clear plasma LDL and result in increased plasma LDL levels. Similarly, point mutations in the gene coding for apolipoprotein B (APOB) also reduce LDL clearance, resulting in the disorder familial defective apolipoprotein B, which is clinically indistinguishable from FH. In 2003, a third FH locus located on chromosome 1, encoding proprotein convertase subtilisin/kexin 9 (PCSK9) was identified. The phenotypes caused by mutations in LDLR, APOB, or PCSK9 are clinically indistinguishable and all characterized by elevated levels of plasma LDL cholesterol and premature coronary artery disease.

The homozygous form of familial hypercholesterolemia (HoFH) with autosomal dominant transmission, in which case both alleles of either LDLR, APOB, or PCSK9 gene are defective, is a rare genetic disorder with prevalence estimated to be one per million population. Patients with HoFH have an extremely rapid accumulation of atherosclerosis with most experiencing xanthomas and severe vascular disease by adolescence or early adulthood despite interventions, including LDL apheresis, which led to the recent Food and Drug Administration approval of 2 novel therapies, lomitapide and mipomersen, specifically for HoFH. Heterozygous familial hypercholesterolemia (HeFH), in which only one allele of LDLR, APOB or PCSK9 gene is defective, has a prevalence of approximately one in 500 individuals, making it one of the most common inherited disorders. Reduction of elevated cholesterol levels in FH individuals can result in a significant reduction of cardiovascular mortality and morbidity, as a large number of landmark clinical trials with cholesterol synthesis inhibitors have clearly demonstrated. However, less than 10% of patients with HeFH are diagnosed and less than 25% are treated with LDL-lowering medications.

Large scale genetic screening for active FH cases finding has been performed in the Netherlands, Spain, Norway and Wales. However, the FH population and prevalence in Taiwan have never been formally studied. Patients are usually not under appropriate treatment owing to lack of standardized diagnostic tool and treatment strategy for FH. Moreover, with the emerging of new classes of LLTs, including microsomal triglyceride transfer protein (MTP) inhibitor, antisense oligonucleotide inhibitor, and PCSK9 inhibitors, even homozygous FH patients now have better chance to be treated to reach recommended treatment goals. Therefore, A National FH registry is needed to collect contemporary data on diagnosis, treatment and outcomes with long- term goals of improving diagnosis, management, and reduction of unnecessary cardiovascular events in FH population in Taiwan.

• Study Type: Observational
• Enrollment (Anticipated): 1000

Contacts and Locations

Study Locations

• Taiwan
  • Taipei, Taiwan
    • Recruiting
    • NTUH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: ADULT; OLDER_ADULT; CHILD
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

Potentially eligible patients will be invited for a screening visit. Written informed consent will be obtained from all patients, and the study will be approved by the institutional review board.

1000 Subjects (estimated) with diagnosis of definite or probable FH, including both heterozygous and homozygous FH, using Taiwan FH Diagnostic Criteria will be recruited for enrollment and clinically followed for at least three years. Taiwan FH Diagnostic Criteria was revised from Dutch Lipid Clinic Network (DLCN) Criteria with consensus of experts in cardiology, genetic, and metabolism specialty, and published by Taiwan Society of Lipids & Atherosclerosis in 2014.

Description

Inclusion Criteria:

• Taiwan FH Diagnostic Criteria was revised from Dutch Lipid Clinic Network (DLCN) Criteria with consensus of experts in cardiology, genetic, and metabolism specialty, and published by Taiwan Society of Lipids & Atherosclerosis in 2014.

Exclusion Criteria:

• The main exclusion criteria will be secondary causes of hyperlipidemia other than FH (i.e. untreated hypothyroidism, nephrotic syndrome), hemodynamically significant valvular or congenital heart disease, life-threatening malignancy, treatment with immunosuppressive agents, or any condition or situation which, in the opinion of the investigator, might be not suitable for this registration.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite cardiovascular outcome	The composite cardiovascular (CV) outcome will be any CV events (coronary, cerebral, or peripheral vascular diseases)	3 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
With at least 1 cardiovascular risk factor.	no evidence of atherosclerotic vascular diseases,with at least 1 cardiovascular risk factor.	3 years

Collaborators and Investigators

• Sponsor: National Taiwan University Hospital

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2015
• Primary Completion (ANTICIPATED): June 1, 2018
• Study Completion (ANTICIPATED): June 1, 2018

Study Registration Dates

• First Submitted: May 11, 2017
• First Submitted That Met QC Criteria: May 11, 2017
• First Posted (ACTUAL): May 15, 2017

Study Record Updates

• Last Update Posted (ACTUAL): May 15, 2017
• Last Update Submitted That Met QC Criteria: May 11, 2017
• Last Verified: September 1, 2016

More Information

Terms related to this study

• Keywords: Familial hypercholesterolemia; low-density lipoprotein cholesterol; total cholesterol; tendon xanthomas; premature atherosclerosis
• Additional Relevant MeSH Terms: Metabolic Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Hypercholesterolemia; Hyperlipoproteinemia Type II
• Other Study ID Numbers: 201505031RIND

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No