Cascade Testing In Identifying At-risk Family Members Of Individuals With Familial Hypercholesterolemia (FH) In PCP

A Cluster Randomized Controlled Trial To Evaluate The Efficacy Of Cascade Testing In Identifying At-risk Family Members Of Individuals With Familial Hypercholesterolemia (FH) In PCP

The purpose of this study is to evaluate the effectiveness of two models of cascade testing in identifying at-risk family members of individuals diagnosed with familial hypercholesterolemia (FH).

Study Overview

• Status: Not yet recruiting
• Conditions: Familial Hypercholesterolemia
• Intervention / Treatment: Other: Standard of Care; Other: Cascade testing

Detailed Description

1. Index Patient Genetic Testing (only index patients from the REP database):

   • Index patients identified through the REP database will undergo confirmatory FH testing HCHLG panel
   • A sputum collection kit is mailed to participants along with a pre-addressed return mailer.
   • Results are recorded in the electronic medical record and communicated to index (REP) participants with next-step instructions.
   • Only index patients with confirmed pathogenic/likely pathogenic variants proceed in the study.

2. Relative Genetic Testing:

   • Relatives in the intervention arm who contact the study team and consent will be mailed a Focused Molecular Targeted Test (FMTT) sputum kit.
   • Testing targets the specific FH variant identified in the corresponding index patient.
   • Testing costs are covered **only** for relatives in the intervention arm.
   • Control arm relatives may choose to pursue clinical genetic testing independently through their primary care provider referring them to genetic counselling (usual care).

3. Baseline Data Collection (Index Patients):

   • Collection of demographics and FH-related history via REDCap.
   • LDL-C values abstracted from EMR; ROI used if external records are required.

4. Randomization:

   • Index patients randomized 2:1 to intervention or control arm.
   • Randomization occurs only after completion of baseline survey.

5. Intervention Arm Procedures:

   Indirect contact:

   In the CASCADE-FH trial, index patients receive IRB-approved recruitment letters, with contact information for the primary care study team, to distribute to up to three first- or second-degree relatives. Relatives who contact the team undergo screening and electronic consent. In this study, index patients choosing the indirect pathway are provided with structured Mayo approved educational materials to support the index patient in accurate and consistent communication with relatives.

   Direct Contact:

   In the CASCADE-FH trial, modified direct contact is operationalized through an IRB approved recruitment letter sent by the index patient to their relatives with contact information for the primary care study team. No direct outreach from the study team occurs unless a relative independently initiates contact to the study team.

   Relatives who contact the team undergo screening and electronic consent. After consent the primary care study team will be able to provide direct support to the at-risk relatives, provide Mayo-approved patient educational materials, and inform them of their potential risk for FH and the opportunity for genetic testing. This approach allows the primary care study team to provide a more direct method of communication and interaction with the at-risk relatives. The study team will also facilitate genetic testing, should the relative wish to proceed with genetic testing for FH.

   • Intervention-arm relatives receive FMTT sputum kits paid for by the study.

6. Control Arm Procedures:

   • Index patients receive usual care. No structured outreach is provided.
   • Relatives may seek genetic testing for FH through their primary care provider referring them to genetic counselling.
   • The study does not cover genetic counseling or testing costs in the control arm.

7. Relative Procedures (All Arms):

   • Relatives who contact the research team receive full study information and undergo screening and consent.
   • Baseline surveys collected via REDCap.
   • Minors require parental consent and age-appropriate assent.

8. Follow-Up Surveys:

   • Index patients and relatives receive surveys at 1, 3, and 12 months via REDCap.
   • Up to two reminder emails are sent approximately 7 days apart.
   • Participants who do not respond after reminders are classified as lost to follow-up.

9. Genetic Testing Workflow:

   • Returned sputum kits will be processed.
   • Results entered into EMR for all participants.

   • index (REP) participants and relatives in the intervention arm are notified via secure message or email on next steps.

     • Index (REP) participants who test positive are instructed to follow up with their primary care provider.
     • Follow-up for Positive Findings for Relatives in the intervention arm:

Participants who receive a pathogenic or likely pathogenic result for FH will be notified via secure patient portal or email. Notifications will instruct the participant to contact their primary care provider for referral to genetic counseling and/or preventive cardiology.

Parents or guardians of minors aged 1-18 years who test positive will be instructed to contact the child's primary care provider to obtain referral to a pediatric endocrinologist.

• Study Type: Interventional
• Enrollment (Estimated): 480
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Family Medicine Research Study Coordinators; Phone Number: 507-422-6823; Email: RSTFMSC@mayo.edu

Study Locations

• United States
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic in Rochester
      • Contact: Family Medicine Research Study Coordinators; Phone Number: 507-422-6823; Email: RSTFMSC@mayo.edu
      • Principal Investigator: Elisa J. Houwink, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Index Patients:

• Age ≥ 18 years.
• Confirmed FH diagnosis using Dutch Lipid Clinic Network criteria *or* genetic confirmation.
• Identified through REP or Tapestry databases.
• Able and willing to provide informed consent.
• At least one eligible first- or second-degree relative.
• Access to and active use of email (computer literacy requirement).

Relatives:

• First- or second-degree relative of an enrolled index patient.
• Age ≥ 1 year (minors require parental consent + assent).
• Willing to participate and able to complete electronic consent (guardian-assisted if minor).
• Access to and active use of email (guardian).

Exclusion Criteria:

Index Patients:

• No confirmed FH diagnosis.
• Insufficient clinical follow-up (<5 years).
• No identifiable or contactable relatives.
• Prior participation in structured cascade testing.
• Severe cognitive impairment preventing informed consent.

Relatives:

• Prior participation in structured cascade testing.
• Severe cognitive impairment preventing informed consent.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Usual Care; Patients will receive standard of care support	Other: Standard of Care; No structured outreach is provided to patient or family members. Relatives may have their primary care provider refer them to genetic counseling services for cascade testing coordination.
Experimental: Structured Outreach; Patients and relatives will receive outreach in the form of direct or indirect contact	Other: Cascade testing; Patient relatives will be contacted either directly or indirectly per patient preference: The indirect contact method provides patients with structured Mayo approved educational materials to support the index patient in accurate and consistent communication with relatives. Relatives have the option to contact the study team for cascade genetic testing. The direct contact method provides patients with a letter inviting relatives to contact the study team. After contact, relatives are offered educational materials and the opportunity for cascade genetic testing.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Genetic testing among first- and second-degree relatives within 12 months of index patient enrollment	Defined as total number of relations to complete CLIA-certified FH test (LDLR, APOB, PCSK9, LDLRAP1) with result returned to the primary care research team.	2 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of newly diagnosed FH cases among relatives	Total number of patient relatives newly diagnosed with familial hypercholesterolemia (FH)	2 years
Time from index patient enrollment (Tapestry identified participants) and diagnosis (REP identified and FH genetic test confirmation) to relative testing	Number of days between patient enrollment and testing of relatives	2 years
Time from relative diagnosis to treatment initiation	Number of days between diagnosis and start of treatment	2 years
Communication modality preference	letter sent by the index patient to their relatives with contact information for the primary care study team. the indirect pathway are provided with structured Mayo approved educational materials to support the index patient in accurate and consistent communication with relatives.	2 years
Referral completion (genetics, cardiology, preventive cardiology) within 6 months of positive result	Number of patients to be referred to specialty within 6 months of positive result	2 years
Cascade depth (degree of relatives reached)	Degree of relatives reached (1st, 2nd, 3rd)	2 years

Collaborators and Investigators

• Sponsor: Mayo Clinic
• Investigators: Principal Investigator: Elisa J. Houwink, MD, PhD, Mayo Clinic

Publications and helpful links

Helpful Links

• Mayo Clinic Clinical Trials

Study record dates

Study Major Dates

• Study Start (Estimated): June 20, 2026
• Primary Completion (Estimated): June 20, 2028
• Study Completion (Estimated): September 20, 2029

Study Registration Dates

• First Submitted: June 2, 2026
• First Submitted That Met QC Criteria: June 12, 2026
• First Posted (Actual): June 17, 2026

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: June 12, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Hyperlipidemias; Dyslipidemias; Lipid Metabolism Disorders; Lipid Metabolism, Inborn Errors; Hyperlipoproteinemias; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Hyperlipoproteinemia Type II; Health Services Administration; Health Care Quality, Access, and Evaluation; Quality of Health Care; Quality Indicators, Health Care; Standard of Care
• Other Study ID Numbers: 26-001620

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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