Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers

NCT ID: NCT05489549

Last Updated: 2025-06-04

Basic Information

• Recruitment Status: RECRUITING
• Total Enrollment: 500 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2022-11-21
• Study Completion Date: 2027-06-30

Brief Summary

Approximately 1.5 million of the 44 million Blacks in the United States are carriers of the valine-to-isoleucine substitution at position 122 (V122I) in the transthyretin (TTR) protein. Virtually exclusive to Blacks, this is the most common cause of hereditary cardiac amyloidosis (hATTR-CA) worldwide. hATTR-CA leads to worsening heart failure (HF) and premature death. Fortunately, new therapies that stabilize TTR improve morbidity and mortality in hATTR-CA, especially when prescribed early in the disease. However, hATTR-CA is often diagnosed at an advanced stage and conventional diagnostic tools lack diagnostic specificity to detect early disease.

The overall objectives of this study are to determine the presence of subclinical hATTR-CA and to identify biomarkers that indicate amyloid progression in V122I TTR carriers. The central hypothesis of this proposal is that hATTR-CA has a long latency period that will be detected through subclinical amyloidosis imaging and biomarker phenotyping.

The central hypothesis will be tested by pursuing 2 specific aims: Aim 1) determine the association of V122I TTR carrier status with CMRI evidence of amyloid infiltration; Sub-aim 1) determine the association of V122I TTR carrier status with cardiac reserve; Aim 2) determine the association between amyloid-specific biomarkers and V122I TTR carrier status; and Sub-aim 2) determine the association of amyloid-specific biomarkers with imaging-based parameters and evaluate their diagnostic utility for identifying subclinical hATTR-CA. In Aim 1, CMRI will be used to compare metrics associated with cardiac amyloid infiltration between a cohort of V122I TTR carriers without HF formed by cascade genetic testing and age-, sex-, and race-matched non-carrier controls. For Sub-Aim 1, a sub-sample of carriers and non-carrier controls enrolled in Aim 1 will undergo novel exercise CMRI to measure and compare cardiac systolic and diastolic reserve. Aim 2 involves measuring and comparing amyloid-specific biomarkers in V122I TTR carriers without HF with samples matched non-carriers (both from Aim 1) and individuals with symptomatic V122I hATTR-CA from our clinical sites. These biomarkers detect and quantify different processes of TTR amyloidogenesis and include circulating TTR, retinol binding protein 4, TTR kinetic stability, and misfolded TTR oligomers. Sub-aim 2 will establish the role of these biomarkers to detect imaging evidence of subclinical hATTR-CA disease.

Conditions

Amyloidosis, Hereditary; Amyloidosis Cardiac; Amyloidosis, Familial; Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy; Transthyretin Gene Mutation

Study Design

• Observational Model Type: CASE_CONTROL
• Study Time Perspective: CROSS_SECTIONAL

Study Groups

V122I TTR carriers

Carriers and controls will undergo standardized, detailed CMRI assessments to test the hypothesis that V122I TTR carrier status will be associated with greater evidence of pathological amyloid progression in comparison with non-carriers.

In addition to the CMRI assessments, carriers and controls enrolled at UT Southwestern will undergo standardized exercise CMRI assessments during the same study visit.

V122I TTR carriers will undergo detailed biomarker assessments. These will be compared with controls and patients with symptomatic V122I hATTR-CA .

No interventions assigned to this group

Age-, sex-, and race-matched non-carrier controls

Carriers and controls will undergo standardized, detailed CMRI assessments to test the hypothesis that V122I TTR carrier status will be associated with greater evidence of pathological amyloid progression in comparison with non-carriers.

In addition to the CMRI assessments, carriers and controls enrolled at UT Southwestern will undergo standardized exercise CMRI assessments during the same study visit.

Controls will undergo detailed biomarker assessments. These will be compared with V122I TTR carriers and patients with symptomatic V122I hATTR-CA .

No interventions assigned to this group

Patients with symptomatic V122I hATTR-CA

Patients with symptomatic V122I hATTR-CA will undergo detailed biomarker assessments. These will be compared with V122I TTR carriers and controls.

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Men and women ages 30-80 who are V122I TTR carriers (or matched non-carriers) without history of HF (this will be assessed by study personnel) and defined as: a) No history of hospitalization within the previous 12 months for management of HF; b) Without an elevated B-type natriuretic peptide level ≥100 pg/mL or NT-proBNP ≥360 pg/mL within the previous 12 months; or c) No clinical diagnosis of HF from a treating clinician
• Signed informed consent

• Men and women ages 30-80 who have symptomatic V122I hATTR-CA as determined by a history of HF (this will be assessed by study personnel) and defined as: a) History of hospitalization within the previous 12 months for management of HF; b) An elevated B-type natriuretic peptide level ≥100 pg/mL or NT-proBNP ≥360 pg/mL within the previous 12 months; or c) A clinical diagnosis of HF from a treating clinician.
• Have an established or suspected diagnosis of hATTR-CA based on either a) Biopsy confirmed by Congo red (or equivalent) staining with tissue typing with immunohistochemistry or mass spectrometric analysis or immunoelectron microscopy, OR b) positive technetium-99m (99mTc)-pyrophosphate or -bisphosphonate scan, combined with accepted laboratory criteria without abnormal M-protein.
• TTR gene sequencing that is pending or that is confirming the V122I variant
• Signed informed consent

Exclusion Criteria

• A self-reported history or clinical history of HF
• Other known causes of cardiomyopathy
• History of light-chain cardiac amyloidosis
• Prior type 1 myocardial infarction (non-ST segment elevation myocardial Infarction {NSTEMI} or ST-elevation myocardial infarction {STEMI})
• Cardiac transplantation
• Body weight >250 lbs
• Estimated glomerular filtration rate ≤30 mL/min/1.73 m2
• Inability to safely undergo CMRI

(For participants with symptomatic V122I hATTR-CA, we will enroll probands with HF from Aim 1 or patients with suspected symptomatic V122I hATTR-CA from the three study sites.)

• Other known causes of cardiomyopathy
• History of light-chain cardiac amyloidosis
• Cardiac transplantation
• Liver transplantation
• Previous treatment with a TTR stabilizer (tafamidis, acoramidis) within the prior 14 days or TTR any silencer (inotersen, patisiran, eplontersen)
• Estimated glomerular filtration rate ≤30 mL/min/1.73 m2

• Minimum Eligible Age: 30 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

The Cleveland Clinic

OTHER

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: collaborator

The University of Texas at Arlington

OTHER

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Texas Southwestern Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Justin Grodin

Associate Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Justin L Grodin, MD MPH

Role: PRINCIPAL_INVESTIGATOR

UT Southwestern

Locations

Columbia University Medical Center

New York, New York, United States

Site Status: RECRUITING

Cleveland Clinic

Cleveland, Ohio, United States

Site Status: RECRUITING

University of Texas Southwestern Medical Center

Dallas, Texas, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Amy Browning

Role: CONTACT

Amy.Browning@utsouthwestern.edu

214-645-8040

Lori R Roth, MS, PAC

Role: CONTACT

Lori.Roth@utsouthwestern.edu

214-645-1043

Facility Contacts

Samantha Guadalupe, MHA

Role: primary

slg2172@cumc.columbia.edu

212-932-4537

Jeffeny De Los Santos, MHA

Role: backup

jd3456@cumc.columbia.edu

(212) 932-4047

Timothy Engelman

Role: primary

engelmt@ccf.org

Role: backup

216-636-6153

Amy Browning

Role: primary

Amy.Browning@utsouthwestern.edu

214-645-8040

Other Identifiers

1R01HL160892-01A1

Identifier Type: NIH

Identifier Source: secondary_id

View Link

STU-2022-0404

Identifier Type: -

Identifier Source: org_study_id