Is Family Screening Improved by Genetic Testing of Familial Hypercholesterolemia

Hypercholesterolemia, Familial Clinical Trial

— IFIGhTFH  

Official title:

Is Family Screening Improved by Genetic Testing of Familial Hypercholesterolemia

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04526457
• Other study ID #: 820969
• Status: Completed
• Phase: N/A
• Start date: November 1, 2014
• Est. completion date: April 1, 2017

Study information

• Verified date: December 2020
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To test the hypothesis that in patients with a clinical diagnosis of familial hypercholesterolemia (FH), genetic testing and identification of a causative mutation might enhance the success of family-based cascade screening.

Description:

To examine the impact of genetic testing on the efficiency of cascade screening for FH, patients with suspected FH or a clinical diagnosis of FH have been randomized to genetic testing or standard of care with lipid testing alone. After systematic encouragement of family enrollment, as a primary endpoint, the compared the number of probands with relatives enrolled in each group one year after results were returned to probands. The secondary endpoints examined include the number of relatives enrolled within 52 weeks of the genetic counseling call and the number of relatives diagnosed with FH through the study. Exploratory subgroup analyses were conducted stratifying the cohort by randomization/genetic test result. Further exploratory analyses compared probands' perceptions about high cholesterol diagnosis at baseline and at 20 weeks from enrollment

Recruitment information / eligibility

• Status: Completed
• Enrollment: 240
• Est. completion date: April 1, 2017
• Est. primary completion date: December 1, 2016
• Accepts healthy volunteers: No
• Gender: All
• Age group: 10 Years and older

Eligibility

Inclusion Criteria:

• For probands, inclusion criteria are as follows:

1. LDL cholesterol > 220 mg/dL or a previous clinical diagnosis of FH

2. Aged 18 years or older

3. Ability to provide informed consent

4. Willingness/ability to contact a minimum of 2 biological relatives about the study

Exclusion Criteria:

• For family members of probands, inclusion criteria are as follows:

1. Willingness to participate in the study

2. Age 10 or older

3. Ability to give informed consent/assent

Related Conditions & MeSH terms

• Hypercholesterolemia
• Hypercholesterolemia, Familial
• Hyperlipoproteinemia Type II

Intervention

Other:
• Standard of Care
Randomized to standard of care with lipid testing only.
• Genetic Testing
Randomized to genetic testing.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of Pennsylvania

References & Publications (16)

Abul-Husn NS, Manickam K, Jones LK, Wright EA, Hartzel DN, Gonzaga-Jauregui C, O'Dushlaine C, Leader JB, Lester Kirchner H, Lindbuchler DM, Barr ML, Giovanni MA, Ritchie MD, Overton JD, Reid JG, Metpally RP, Wardeh AH, Borecki IB, Yancopoulos GD, Baras A, Shuldiner AR, Gottesman O, Ledbetter DH, Carey DJ, Dewey FE, Murray MF. Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science. 2016 Dec 23;354(6319). pii: aaf7000. doi: 10.1126/science.aaf7000. — View Citation

Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012 Nov;97(11):3956-64. doi: 10.1210/jc.2012-1563. Epub 2012 Aug 14. Erratum in: J Clin Endocrinol Metab. 2014 Dec;99(12):4758-9. — View Citation

CDC. Genomic tests by levels of evidence. Centers for Disease Control Office of Public Health Genomics. http://www.cdc.gov/genomics/gtesting/file/print/tier.pdf. Published 2013. Accessed August 23, 2016.

De Backer G, Besseling J, Chapman J, Hovingh GK, Kastelein JJ, Kotseva K, Ray K, Reiner Ž, Wood D, De Bacquer D; EUROASPIRE Investigators. Prevalence and management of familial hypercholesterolaemia in coronary patients: An analysis of EUROASPIRE IV, a study of the European Society of Cardiology. Atherosclerosis. 2015 Jul;241(1):169-75. doi: 10.1016/j.atherosclerosis.2015.04.809. Epub 2015 Apr 30. — View Citation

deGoma EM, Ahmad ZS, O'Brien EC, Kindt I, Shrader P, Newman CB, Pokharel Y, Baum SJ, Hemphill LC, Hudgins LC, Ahmed CD, Gidding SS, Duffy D, Neal W, Wilemon K, Roe MT, Rader DJ, Ballantyne CM, Linton MF, Duell PB, Shapiro MD, Moriarty PM, Knowles JW. Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry. Circ Cardiovasc Genet. 2016 Jun;9(3):240-9. doi: 10.1161/CIRCGENETICS.116.001381. Epub 2016 Mar 24. — View Citation

Knowles JW, Rader DJ, Khoury MJ. Cascade Screening for Familial Hypercholesterolemia and the Use of Genetic Testing. JAMA. 2017 Jul 25;318(4):381-382. doi: 10.1001/jama.2017.8543. — View Citation

Leren TP, Finborud TH, Manshaus TE, Ose L, Berge KE. Diagnosis of familial hypercholesterolemia in general practice using clinical diagnostic criteria or genetic testing as part of cascade genetic screening. Community Genet. 2008;11(1):26-35. doi: 10.1159/000111637. Epub 2008 Jan 15. — View Citation

Mortensen MB, Kulenovic I, Klausen IC, Falk E. Familial hypercholesterolemia among unselected contemporary patients presenting with first myocardial infarction: Prevalence, risk factor burden, and impact on age at presentation. J Clin Lipidol. 2016 Sep-Oct;10(5):1145-1152.e1. doi: 10.1016/j.jacl.2016.06.002. Epub 2016 Jun 14. — View Citation

Nherera L, Marks D, Minhas R, Thorogood M, Humphries SE. Probabilistic cost-effectiveness analysis of cascade screening for familial hypercholesterolaemia using alternative diagnostic and identification strategies. Heart. 2011 Jul;97(14):1175-81. doi: 10.1136/hrt.2010.213975. — View Citation

Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Borén J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013 Dec;34(45):3478-90a. doi: 10.1093/eurheartj/eht273. Epub 2013 Aug 15. — View Citation

Pang J, Poulter EB, Bell DA, Bates TR, Jefferson VL, Hillis GS, Schultz CJ, Watts GF. Frequency of familial hypercholesterolemia in patients with early-onset coronary artery disease admitted to a coronary care unit. J Clin Lipidol. 2015 Sep-Oct;9(5):703-8. doi: 10.1016/j.jacl.2015.07.005. Epub 2015 Jul 18. — View Citation

Programme WHOHG. Familial hypercholesterolaemia (FH) : report of a second WHO consultation, Geneva, 4 September 1998. 1999:This report is dedicated to the memory of Professo.

Stone NJ, Robinson JG, Lichtenstein AH, Bairey Merz CN, Blum CB, Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson K, Wilson PW; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):2889-934. doi: 10.1016/j.jacc.2013.11.002. Epub 2013 Nov 12. Erratum in: J Am Coll Cardiol. 2014 Jul 1;63(25 Pt B):3024-3025. J Am Coll Cardiol. 2015 Dec 22;66(24):2812. — View Citation

Sturm AC, Knowles JW, Gidding SS, Ahmad ZS, Ahmed CD, Ballantyne CM, Baum SJ, Bourbon M, Carrié A, Cuchel M, de Ferranti SD, Defesche JC, Freiberger T, Hershberger RE, Hovingh GK, Karayan L, Kastelein JJP, Kindt I, Lane SR, Leigh SE, Linton MF, Mata P, Neal WA, Nordestgaard BG, Santos RD, Harada-Shiba M, Sijbrands EJ, Stitziel NO, Yamashita S, Wilemon KA, Ledbetter DH, Rader DJ; Convened by the Familial Hypercholesterolemia Foundation. Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel. J Am Coll Cardiol. 2018 Aug 7;72(6):662-680. doi: 10.1016/j.jacc.2018.05.044. Review. — View Citation

Umans-Eckenhausen MA, Defesche JC, Sijbrands EJ, Scheerder RL, Kastelein JJ. Review of first 5 years of screening for familial hypercholesterolaemia in the Netherlands. Lancet. 2001 Jan 20;357(9251):165-8. — View Citation

Wald DS, Bangash FA, Bestwick JP. Prevalence of DNA-confirmed familial hypercholesterolaemia in young patients with myocardial infarction. Eur J Intern Med. 2015 Mar;26(2):127-30. doi: 10.1016/j.ejim.2015.01.014. Epub 2015 Feb 11. — View Citation

* Note: There are 16 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Proband perceptions about their high cholesterol including its etiology, management and heritability at 20 weeks after enrollment compared to baseline	Proband perceptions about their high cholesterol including its etiology, management and heritability were examined at baseline and 20 weeks after enrollment, using a questionnaire administered at these time points. Investigators examined proband agreement/disagreement with statements about the etiology of their high cholesterol, its management and heritability in these questionnaires. Using this approach, investigators were able to determine the proportion of probands that agreed/disagreed with these statements, and could compare how these proportions differed between the groups of interest at baseline/follow-up and how these changed from baseline to follow-up.	20 weeks after enrollment
Primary	Number of probands with relatives enrolled	The primary outcome of this study was the number of probands with family members enrolled in the study within 52 weeks of results being returned to probands. Investigators compared the proportion of probands with a relative enrolled in the genetic testing group with the proportion of probands with a relative enrolled in the usual care group (lipid testing only). Relative enrolment was defined as the return of a test kit within the study time frame.	52 weeks after genetic/lipid testing results are returned to probands
Secondary	The number of relatives enrolled in the study 52 weeks after results were returned to probands	The number of relatives enrolled in the study within 52 weeks of results being returned to probands. Investigators compared the number of relatives enrolled in the genetic testing group with the number of relatives enrolled in the usual care group (lipid testing only). Relative enrolment was defined as the return of a test kit within the study time frame.	52 weeks after results are returned to probands
Secondary	The number of family members diagnosed with FH 52 weeks after results were returned to probands	The number of family members diagnosed with FH within 52 weeks of results being returned to probands. Investigators compared the number of enrolled relatives diagnosed with FH in the genetic testing group with the number of enrolled relatives diagnosed with FH in the usual care group (lipid testing only). This diagnosis had to be made through the study. The number of enrolled relatives diagnosed with FH in each group was expressed as the new case per index case ratio (relatives diagnosed with FH/total number of index case). Relative enrolment was defined as the return of a test kit within the study time frame. The diagnosis of FH was based on meeting either genetic or the Make Early Diagnosis To Prevent Early Deaths (MEDPED) clinical criteria	52 weeks after results are returned to probands