- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02354079
HYPOCHOL : A Genetically-based Strategy to Identify New Targets in Cholesterol Metabolism (HYPOCHOL)
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
The goal is to recruit 400 subjects: 200 adult subjects with familial hypobetalipoproteinemia (FHBL) (index cases) plus 200 additional related subjects in at least 10 large informative FHBL families, in which there is no known mutation in FHBL genes.
The patient care is modified: patient will have an Hospital Anxiety and Depression (HAD) questionnaire (focus on depressive syndrome), a food diary, and some additional blood analysis (including genetic analysis).
One of the main issue to recruit FHBL patients is the fact that they are asymptomatic and that FHBL is not identified as a serious illness by their general physicians.
Step-1. Excluding mutations in selected candidate genes As a first approach to screen candidate genes and exclude patients with known mutations, the investigators developed a custom design based on the Haloplex™ technology (Agilent® Technologies) to perform high-throughput sequencing of the coding regions of 10 genes, including those previously described in FHBL (apolipoprotein B (APOB), Proprotein convertase subtilisin/kexin type 9 (PCSK9)), Microsomal triglyceride transfer protein (MTP or ABL), chylomicron retention disease (CMRD), Secretion associated, Ras related GTPase (SARA2 gene), as well as 6 additional candidate genes in cholesterol metabolism (low density lipoprotein receptor (LDLR), Sortilin (SORT1), Inducible Degrader of the LDL receptor (IDOL), Cholesteryl ester transfer protein (CETP), Apolipoprotein E (ApoE) and Angiopoietin-like Protein 3 (ANGTPL3)). All the recruited index cases (n=200) will be genotyped to select only those without mutations in previously described genes, being approximately 50% of our index case cohort.
Step-2. Identification of informative families and exome sequencing In patients without identified mutations, the investigators will conduct a familial screening in order to identify other cases of FHBL among proband relatives. An analysis of fasting plasma lipid parameters (total cholesterol (TC), High density lipoprotein cholesterol (HDL-C), Low-Density Lipoproteins (LDL-C) and triglycerides (TG)) will be performed for each related. Affected subjects will be determined by a spontaneous LDL-C < 80 mg/dl and/or apoB < 50 mg/dl. In contrast, non-affected subjects will display LDL-C > 80 mg/dl and/or apoB > 50 mg/dl.
For large families, the investigators will then combine whole-exome sequencing and linkage analysis to identify any novel genetic variant likely explaining FHBL. Depending on family pedigree, whole-exome sequencing (WES) will be performed on 2 to 5 patients per family. All relatives will be genotyped for linkage analysis.
In parallel to this genetic approach, a regional epidemiological analysis will be performed to identify some geographical clusters with a high prevalence of the disease, as developed in the project named VaCaRMe (for Vascular and Cardiac, Respiratory and Metabolic overcome diseases)
An additional aim, based on an exhaustive phenotyping of FHBL patients, is to investigate the safety of very low LDL-C and to perform some genotype-phenotype correlations in patients with FHBL population."
Study Type
Enrollment (Actual)
Phase
- Not Applicable
Contacts and Locations
Study Locations
-
-
-
Nantes, France, 44093
- Chu De Nantes
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
- Child
- Adult
- Older Adult
Accepts Healthy Volunteers
Description
Inclusion Criteria:
For index cases without family screening:
o Patient with HBL: fasting LDL-C ≤ 50 mg/dl.
For familial affected cases:
- Relative with HBL: fasting LDL-C ≤ 80 mg/dl and/or Apo B ≤ 50 mg/dl and at least one related family case suffering from HBL.
All subjects, including familial non-affected cases, must give written consent (dated and signed) to participate at the constitution of biobank (including DNA samples and urine samples).
Exclusion Criteria:
- Use of lipid-lowering drugs (statins, fibrates, ezetimibe, bile-acid sequestering resin) or nutraceuticals known to affect lipids (red yeast rice, margarine and dairy with plant sterol)
- Patient screened within an extreme metabolic disturbance (emergency situations, sepsis, hospitalization in intensive care unit)
- Patients with hyperthyroidism, severe liver failure, end stage chronic kidney disease, serious pancreatic failure, anemia related to thalassemia or sickle cell disease, strict vegan diet or malnutrition
- Refusal of the patient or his legal representative to participate in the study"
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Other
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Other: genetic analysis
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
type and number of genetic abnormalities leading to FHBL
Time Frame: ten years
|
To identify new gene involved in FHBL and determine genetic cause of FHBL (Patients with FHBL and their relatives will be recruited to establish familial forms of FHBL in large informative families with no mutations in known classical FHBL genes.
This will allow perform genetic analysis using new approaches to genetic broadband (exome sequencing analysis + linkage analysis).
This approach will allow specify which chromosomal regions are shared only by affected individuals, and identify new candidate genes).
|
ten years
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
number of phenotypes associated to genotype of FHBL and very low LDL-C
Time Frame: ten years
|
To determine number of phenotypes associated to genotype of FHBL and very low LDL-C.
(Liver steatosis, Glucose homeostasis, Cancer, Depression scores, Cardiovascular diseases).
|
ten years
|
Collaborators and Investigators
Sponsor
Investigators
- Principal Investigator: Charlotte AUTHIER, Doctor, Health Care Centers of French Health Insurance in Saint-Nazaire
- Principal Investigator: Didier GOXE, Health Care Centers of French Health Insurance in La Roche sur Yon
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Estimated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimated)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
Other Study ID Numbers
- RC14_0400
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Hypobetalipoproteinemia
-
Marcello ArcaPfizer; Göteborg University; University of HelsinkiNot yet recruitingFamilial Hypobetalipoproteinemia | Familial Hypobetalipoproteinemia - Heterozygous Form
-
Nantes University HospitalCompletedFamilial HypobetalipoproteinemiaFrance
-
Medical University InnsbruckUnknownFamilial Hypobetalipoproteinaemia - Heterozygous Form | Low-LDL-syndromeAustria
-
Hospices Civils de LyonCompleted
-
Nantes University HospitalCompletedHypobetalipoproteinemiaFrance
-
National Heart, Lung, and Blood Institute (NHLBI)CompletedHeart Diseases | Cardiovascular Diseases | Hypobetalipoproteinemia
-
Kastle Therapeutics, LLCIonis Pharmaceuticals, Inc.CompletedMetabolic Diseases | Congenital Abnormalities | Infant, Newborn, Diseases | Genetic Diseases, Inborn | Dyslipidemias | Metabolism, Inborn Errors | Lipid Metabolism Disorders | Hypercholesterolemia | Hyperlipidemias | Lipid Metabolism, Inborn Errors | Hypobetalipoproteinemias | Hypolipoproteinemias | Hypolipopro... and other conditionsNetherlands
Clinical Trials on hypobetalipoproteinemia genetic and genotypic screening
-
Sun Yat-sen UniversityUnknown
-
The University of Texas Health Science Center at...National Institute of General Medical Sciences (NIGMS)RecruitingKidney Neoplasms | Bone Cancer | Thyroid Neoplasms | Pheochromocytoma | Paraganglioma | Other Cancer | Inherited Cancer Syndrome | Associated ConditionsUnited States
-
Federico II UniversitySan Raffaele University Hospital, Italy; San Giuseppe Moscati HospitalRecruitingPeripartum CardiomyopathyItaly
-
CENTOGENE GmbH RostockActive, not recruitingFrontotemporal DementiaItaly, Spain, Belgium, Turkey, Portugal, Germany, Greece
-
University of BaselRecruitingLynch Syndrome | Hereditary Breast and Ovarian CancerSwitzerland
-
NYU Langone HealthRecruitingMLH1 Gene Mutation | RAD51C Gene Mutation | BRIP1 Gene Mutation | MSH6 Gene Mutation | PMS2 Gene Mutation | BRCA-Mutated Ovarian Carcinoma | MSH2 A636P | EPCAMUnited States
-
Assistance Publique - Hôpitaux de ParisCompletedTrisomy 21, 18 and 13 ScreeningFrance
-
ReprogeneticsSuspendedInfertilityUnited States, Spain
-
University Hospital, GhentTerminatedInfertility | Preimplantation Genetic ScreeningBelgium
-
Ohio State University Comprehensive Cancer CenterActive, not recruitingLynch Syndrome | Relatives | Endometrial Carcinoma | Endometrial AdenocarcinomaUnited States