Amyloidosis, HereditaryNCT05489549
Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers
An observational study of Amyloidosis, Hereditary and Amyloidosis Cardiac, run by University of Texas Southwestern Medical Center at 3 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 30 to 80 years
- Conditions the study is for
- Amyloidosis, Hereditary, Amyloidosis Cardiac, Amyloidosis, Familial
- How many people
- 500 participants
- Where
- 3 sitesUnited States
- Study dates
- 21 Nov 2022to 30 Jun 2027
- Phase
- Observational
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 to 80 years
- All sexes
- Adult, Older adult
Study population: For Aim 1, the will be a cross-sectional cohort study of 200 pathogenic TTR allele carriers and 200 age-, sex- and race-matched non-carrier controls without heart failure. For Sub-aim 1, this will be a cross-sectional sub-study of the 2 groups enrolled in Aim 1 at UT Southwestern. For Aim 2, this will be a cross-sectional cohort study of 200 pathogenic TTR allele carriers without HF (see Aim 1, Approach), 200 age-, sex-, and race-matched controls (see Aim 1), and 100 patients with symptomatic hATTR-CA who will undergo detailed biomarker assessments.
Who may be able to join
- Men and women ages 30-80 who are carriers of pathogenic TTR alleles (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 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 pathogenic TTR variant
- Signed informed consent
Who cannot join
- 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
Show all 15Show fewer
- Estimated glomerular filtration rate ≤30 mL/min/1.73 m2
- Inability to safely undergo CMRI
- (For participants with symptomatic hATTR-CA, we will enroll probands with HF from Aim 1 or patients with suspected symptomatic 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
Trial locations and contacts
3 sites in 1 country. Contact the study team or a site near you to ask about taking part.
United States3 sites, 3 recruiting
- Recruiting
Cleveland Clinic
Cleveland, Ohio, 44195
Jennifer (Kirsop) Wilcox, 216-636-6153, kirsopj@ccf.org
216-636-6153
- Recruiting
University of Texas Southwestern Medical Center
Dallas, Texas, 75390
Amy Browning, 214-645-8040, Amy.Browning@utsouthwestern.edu
Justin L Grodin, MD MPH
- Recruiting
Columbia University Medical Center
New York, New York, 10032
Jeffeny De Los Santos, MHA, (212) 932-4047, jd3456@cumc.columbia.edu
Mathew S Maurer, MD
About this study
Official title: Identifying Subclinical Transthyretin Cardiac Amyloidosis in Asymptomatic Carriers of the V122I TTR Allele
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
- Keywords
- Amyloidosis, Transthyretin Amyloidosis, V122I TTR, p.Val142Ile TTR, Cardiac magnetic resonance imaging
- Medical subject headings
- Amyloidosis, Familial, Amyloid Neuropathies, Familial, Amyloidosis, Amyloidosis, Hereditary, Transthyretin-Related
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| 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 . | |
| 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 . | |
| 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. |
What is being measured
The primary outcome is the main question the study is designed to answer.
(Aim 1) Evidence of amyloid infiltration as measured by ECV
ECV expansion represents interstitial expansion from amyloid infiltration and greater levels can distinguish amyloidosis from other hypertrophic cardiomyopathies and correlate with cardiac amyloidosis disease severity.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Sub-aim 1) Δ stroke volume index (ΔSVi)
We will measure and compare ΔSVi (%) from rest to peak stress in V122I TTR carriers and non-carrier controls. Participants will exercise within the bore of the magnet using an MR compatible ergometer with adjustable electronic resistance (Ergospect Cardio-Stepper, Ergospect). Cardiac imaging will be performed at rest and during exercise at 25% (low intensity), 50% (moderate intensity), and 66% (heavy intensity) of maximal predicted work rate. Workloads will be maintained for ~5 min at each stage - 3 min to achieve a physiological steady-state and then 2 minutes for image acquisition.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
Secondary outcomes (20)
(Aim 1) Late gadolinium enhancement
We will use a PSIR sequence, limiting operator-dependency. Global subendocardial enhancement, transmural LGE, and focal, patchy LGE are all features of cardiac amyloidosis, representing interstitial expansion. In cardiac amyloidosis, unlike other cardiomyopathies, LGE is correlated to amyloid infiltration not interstitial fibrosis.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Aim 1) Native T1 and T2 mapping
Native T1 and T2 mapping represent diffuse interstitial expansion and myocardial edema, respectively. Native T1 measurements are abnormally elevated in amyloidosis and much higher in comparison with other cardiomyopathies that may be associated with interstitial expansion.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Aim 1) Post-gadolinium T1 signal intensity
Post-gadolinium T1 signal intensity changes characteristically with myocardial signal nulling before the blood pool signal in amyloidosis (opposite of non-amyloid hearts). We will test for this characteristic pattern using a Look-Locker "TI Scout" sequence.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Aim 1) High resolution cardiac cine imaging for cardiac morphology
High resolution cardiac cine imaging will measure cardiac morphology in all 4 chambers of the heart.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Aim 1) High resolution cardiac cine imaging for global systolic function as ejection fraction
High resolution cardiac cine imaging will measure cardiac systolic function in all 4 chambers of the heart by assessing ejection fraction.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Aim 1) High resolution cardiac cine imaging for global systolic function as fractional area change
High resolution cardiac cine imaging will measure cardiac systolic function in all 4 chambers of the heart by assessing fractional area change.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Aim 1) High resolution cardiac cine imaging for global systolic function via novel feature tracking
High resolution cardiac cine imaging will measure cardiac systolic function in all 4 chambers of the heart using novel feature tracking methods.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Aim 1) High resolution cardiac cine imaging for global diastolic function via novel feature tracking.
High resolution cardiac cine imaging will measure cardiac diastolic function in all 4 chambers of the heart using novel feature tracking methods.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Aim 1) LV strain from magnetic resonance tissue tagging
Magnetic resonance tissue tagging is the gold-standard for measuring LV strain and strain rate, providing highly sensitive measures of subclinical systolic and diastolic function.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Aim 1) Phase contrast MRI to assess diastolic function by measurement of mitral inflow velocities.
Phase contrast MRI will be used to assess LV diastolic function by assessing the ratio of early (E) and late (A) mitral inflow velocities which can be abnormal in V122I TTR carriers which can be abnormal in V122I TTR carriers.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Aim 1) Phase contrast MRI to assess diastolic function by calculating the E/e' strain rate.
Phase contrast MRI will be used to assess LV diastolic function by cine feature tracking and MR tissue tagging to calculate the E/e' strain rate which can be abnormal in V122I TTR carriers.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
(Sub-aim 1) End diastolic volume index (EDVi, ml/m2) in all 4 chambers
Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
(Sub-aim 1) End systolic volume index (ESVi, ml/m2) in all 4 chambers
Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
(Sub-aim 1) Stroke volume index (SVi, ml/m2, ΔSVi is the primary outcome) in all 4 chambers
Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
(Sub-aim 1) Ejection fraction (LVEF, %) in all 4 chambers
Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
(Sub-aim 1) Longitudinal strain (LS, %)
Exercise CMRI will be performed immediately following the resting CMRI protocol described for the Sub-aim 1 primary outcome.
Measured: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
(Aim 2) TTR concentration
Venous blood will be collected by phlebotomy at enrollment for all participants. Both plasma and serum will be isolated and aliquoted for storage. Plasma TTR levels will be measured with commercially available ELISA assays.
Measured: At baseline for all three cohorts
(Aim 2) RBP4 concentration
Venous blood will be collected by phlebotomy at enrollment for all participants. Both plasma and serum will be isolated and aliquoted for storage. Plasma RBP4 levels will be measured with commercially available ELISA assays.
Measured: At baseline for all three cohorts
(Aim 2) Concentration of circulating misfolded TTR oligomers
Venous blood will be collected by phlebotomy at enrollment for all participants. Circulating misfolded TTR oligomers will be measured with peptide-based probes that selectively label these species in plasma.
Measured: At baseline for all three cohorts
(Aim 2) TTR kinetic stability
Venous blood will be collected by phlebotomy at enrollment for all participants. TTR kinetic stability will be measured by using Western Blot techniques.
Measured: At baseline for all three cohorts
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Aug 2022
- Study start21 Nov 2022
- Primary completion30 Jun 2027 (estimated)
- Study completion30 Jun 2027 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Amyloidosis, HereditaryStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 500 participants (estimated)
Sponsor and investigators
- Lead sponsor
- University of Texas Southwestern Medical Center
- Sponsor type
- University, hospital or other
- Collaborators
- The Cleveland Clinic, Columbia University, The University of Texas at Arlington, National Heart, Lung, and Blood Institute (NHLBI)
- Responsible party
- Principal investigator, Justin Grodin, University of Texas Southwestern Medical Center
- Investigators
- Justin L Grodin, MD MPH, Principal investigator, UT Southwestern
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05489549
- Sponsor's protocol ID
- STU-2022-0404
- Other IDs
- 1R01HL160892-01A1
- Status last verified
- Jun 2026
- First submitted
- 29 Jul 2022
- Last updated
- 31 Aug 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided