Direct Contact Genetic Screening for High Cholesterol

Overseen By Amber L Beitelshees, PharmD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: University of Maryland, Baltimore

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 1

200 Participants Needed

Trial Summary

What is the purpose of this trial?

An important aspect of successful genomic medicine implementation is developing effective approaches for screening at-risk family members after probands are identified, also known as cascade screening. Most cascade screening studies conducted to date have been conducted outside the US, and very few studies have used a rigorous approach involving a comparator group or randomized controlled design. A major question in the field is how to most effectively implement cascade screening, given commonly cited communication barriers, while respecting privacy among probands and family members. This study will conduct a randomized controlled trial to assess direct contact of relatives by study team members vs indirect, or proband-initiated, contact. We will assess efficacy of the cascade screening intervention, patient-centered outcomes regarding mental, physical, and psychosocial outcomes in probands and family members, and implementation evaluation outcomes. Individuals who are known to carry the KCNQ1 Met224Thr or APOB Arg3527Gln variant will be eligible to participate. After providing consent and being deemed eligible, individuals will be randomized in a 1:1 manner into the direct or indirect contact of family members arm of the study. The randomization will be stratified by variant to ensure equal representation of each variant in the study arms. Individuals in the indirect arm will be instructed to contact their first-degree family members about the opportunity to be screened. They will be provided with a disease-specific pamphlet and a family letter explaining the cascade screening. In the direct arm, probands will be advised that the study staff will be contacting their family members. They will be instructed to also contact their family members prior to the study team contacting them. Approximately two weeks after this meeting with the proband, the study staff will mail letters to eligible first-degree family members of the probands. If we do not hear back from individual family members, we will follow-up with another letter, telephone call, or home visit. The information contained in the letters will be the same information for both the direct and indirect arms of the study. All interested family members will receive pre-test counseling and free, in-home, saliva-based genetic testing, and post-test counseling.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications.

What data supports the effectiveness of the treatment Direct contact of family members for cascade screening of relevant variants for high cholesterol?

Research shows that cascade screening, which involves testing family members for genetic diseases, is effective in identifying individuals with undiagnosed familial hypercholesterolemia (FH). Direct contact by healthcare providers to inform relatives about their risk has been considered a reasonable approach to improve screening uptake, as some individuals with FH are willing to provide contact information for this purpose. ^{1 2 3 4 5}

Is direct contact genetic screening for high cholesterol safe for humans?

The research does not provide specific safety data for direct contact genetic screening for high cholesterol, but it suggests that genetic cascade screening is a cost-effective and effective method for identifying individuals with familial hypercholesterolemia (FH). ^{1 2 3 4 5}

How does the treatment of direct contact genetic screening for high cholesterol differ from other treatments?

This treatment is unique because it involves directly contacting family members for genetic screening to identify relevant variants associated with high cholesterol, which is a proactive approach to prevent cardiovascular diseases. Unlike traditional treatments that focus on managing symptoms, this method aims to identify at-risk individuals early through family connections, making it a cost-effective strategy for preventing the condition. ^{1 2 4 6 7}

Eligibility Criteria

This trial is for adults who carry the KCNQ1 Met224Thr or APOB Arg3527Gln genetic variant, which can be linked to conditions like Long QT Syndrome and high cholesterol. Their first-degree relatives are also eligible as part of a family-based screening approach.

Inclusion Criteria

I carry the KCNQ1 Thr224Met or APOB R3527Q gene mutation.

I am 18 years old or older.

A close family member has the KCNQ1 Thr224Met or APOB Arg3527Gln mutation.

Exclusion Criteria

N/A

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Randomization and Initial Contact

Participants are randomized into direct or indirect contact arms. Initial contact with family members is made.

2 weeks

1 visit (in-person or virtual)

Cascade Screening

Family members receive pre-test counseling, genetic testing, and post-test counseling.

6 months

In-home visits for genetic testing

Follow-up

Participants are monitored for patient-centered outcomes and implementation evaluation outcomes.

up to 4 years

Treatment Details

Interventions

• Direct contact of family members for cascade screening of relevant variants

Trial Overview The study compares two methods of informing family members about their risk for certain genetic conditions: direct contact by the study team versus indirect contact initiated by the patient (proband). It aims to determine which method is more effective and respectful of privacy.

Participant Groups

Group I: Direct contact Experimental Treatment 1 Intervention

Study team contact of family members

Group II: Indirect contact Active Control 1 Intervention

Proband initiated contact of family members

Who Is Running the Clinical Trial?

University of Maryland, Baltimore

Lead Sponsor

Trials

729

Recruited

540,000+

Findings from Research

The clinical trial aims to compare the effectiveness and cost of cascade screening for familial hypercholesterolemia (FH) in patients with and without identifiable pathogenic variants, involving a total of 50 patients each from groups of definite, probable, and possible FH.

By testing family members of patients with definite FH for pathogenic variants and those with probable/possible FH for lipid profiles, the study seeks to identify new cases of FH, which will help refine screening guidelines and improve early detection of this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of a Controlled Trial of Cascade Screening for Hypercholesterolemia: The (CASH) Study. Kullo, IJ., Bailey, KR.[2023]

In a study of 183 individuals with familial hypercholesterolemia (FH), key predictors for enrolling relatives in genetic screening included the index-case's LDL-cholesterol levels, their knowledge of family history of dyslipidemia, and the referral source, with those referred through a dedicated website showing higher enrollment rates.

The findings suggest that understanding the clinical and socio-economic characteristics of index-cases can help improve strategies for enrolling at-risk individuals in FH screening programs, potentially enhancing early detection and management of this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Predictors of Family Enrollment in a Genetic Cascade Screening Program for Familial Hypercholesterolemia. Silva, PRS., Jannes, CE., Oliveira, TGM., et al.[2019]

Familial hypercholesterolemia (FH) is often underdiagnosed, but early detection through cascade screening can significantly reduce health risks for affected individuals and their families.

A study involving 27 index cases (19 from the U.S. and 8 international) found that a majority are open to allowing healthcare providers to directly contact at-risk relatives, suggesting that direct contact could enhance screening efforts for FH.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Perspectives from individuals with familial hypercholesterolemia on direct contact in cascade screening. Schwiter, R., Brown, E., Murray, B., et al.[2021]

Familial hypercholesterolemia (FH) is a common genetic disorder that leads to high LDL cholesterol levels and increased risk of cardiovascular diseases, yet it remains underdiagnosed globally despite available treatments and genetic testing.

This case study highlights the effectiveness of genetic cascade screening in identifying new FH patients, as it successfully identified three relatives of an index patient with a rare LDLR gene variant, demonstrating its potential for preventing cardiovascular issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phenotypic vs. genetic cascade screening for familial hypercholesterolemia: A case report. Blokhina, AV., Ershova, AI., Meshkov, AN., et al.[2022]

In a study of 46 individuals (31 probands and 15 additional screened individuals) over 8 years, genetic testing revealed that 71% of unrelated probands had distinct LDLR variants linked to familial hypercholesterolemia (FH), highlighting the importance of genetic testing in diagnosing this condition.

Cascade screening identified adults with less severe FH phenotypes who might not have met previous testing criteria, demonstrating its effectiveness in early detection and management of FH cases that could otherwise remain undiagnosed.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic Spectrum and Cascade Screening of Familial Hypercholesterolemia in Routine Clinical Setting in Hong Kong. Yip, MK., Kwan, EY., Leung, JY., et al.[2023]

Population-wide genomic screening for familial hypercholesterolemia (FH) can identify individuals at risk for cardiovascular disease, particularly when conducted at younger ages, such as 20 years old, potentially leading to significant health benefits with 111 quality-adjusted life-years (QALYs) gained per 100,000 individuals screened.

Currently, the cost-effectiveness of FH screening is not favorable, with an incremental cost-effectiveness ratio (ICER) of $181,000 per QALY for 20-year-olds; however, reducing the cost of genomic testing to $100 could improve this to $91,000 per QALY, suggesting that lowering costs or integrating FH screening into broader health initiatives could enhance its value.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of population-wide genomic screening for familial hypercholesterolemia in the United States. Spencer, SJ., Jones, LK., Guzauskas, GF., et al.[2023]

A nurse-led genetic register successfully identified 121 new cases of heterozygous familial hypercholesterolaemia among 200 first-degree relatives tested, highlighting the effectiveness of targeted screening in detecting this condition early.

The study found that many affected individuals were asymptomatic and had high cholesterol levels, indicating that traditional risk factor screening would have missed most cases, suggesting the need for a more proactive genetic testing approach in lipid clinics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia. Bhatnagar, D., Morgan, J., Siddiq, S., et al.[2019]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Design of a Controlled Trial of Cascade Screening for Hypercholesterolemia: The (CASH) Study. [2023]

2. Brazil pubmed.ncbi.nlm.nih.gov

Predictors of Family Enrollment in a Genetic Cascade Screening Program for Familial Hypercholesterolemia. [2019]

3. United States pubmed.ncbi.nlm.nih.gov

Perspectives from individuals with familial hypercholesterolemia on direct contact in cascade screening. [2021]

4. Switzerland pubmed.ncbi.nlm.nih.gov

Phenotypic vs. genetic cascade screening for familial hypercholesterolemia: A case report. [2022]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Genetic Spectrum and Cascade Screening of Familial Hypercholesterolemia in Routine Clinical Setting in Hong Kong. [2023]

6. United States pubmed.ncbi.nlm.nih.gov

Cost-effectiveness of population-wide genomic screening for familial hypercholesterolemia in the United States. [2023]

7. England pubmed.ncbi.nlm.nih.gov

Outcome of case finding among relatives of patients with known heterozygous familial hypercholesterolaemia. [2019]