Clinical trial NCT05489549: Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers
Official title: Identifying Subclinical Transthyretin Cardiac Amyloidosis in Asymptomatic Carriers of the V122I TTR Allele
Study type: OBSERVATIONAL
Overall status: RECRUITING
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
Lead sponsor: University of Texas Southwestern Medical Center
Sponsor class: OTHER
Collaborators: name: The Cleveland Clinic
name: Columbia University
name: The University of Texas at Arlington
name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2022-08-05
Enrollment: 500
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Observational model: CASE_CONTROL
Time perspective: CROSS_SECTIONAL
Sampling method: NON_PROBABILITY_SAMPLE
Study population: For Aim 1, the will be a cross-sectional cohort study of 200 V122I TTR 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 V122I TTR carriers without HF (see Aim 1, Approach), 200 age-, sex-, and race-matched controls (see Aim 1), and 100 patients with symptomatic V122I hATTR-CA who will undergo detailed biomarker assessments.

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.


Eligibility criteria: (V122I TTR carriers (or matched non-carriers))

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

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.)

Inclusion Criteria:

* 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:

* 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

Primary outcomes:
measure: (Aim 1) Evidence of amyloid infiltration as measured by ECV
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Sub-aim 1) Δ stroke volume index (ΔSVi)
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
Secondary outcomes:
measure: (Aim 1) Late gadolinium enhancement
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Aim 1) Native T1 and T2 mapping
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Aim 1) Post-gadolinium T1 signal intensity
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Aim 1) High resolution cardiac cine imaging for cardiac morphology
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Aim 1) High resolution cardiac cine imaging for global systolic function as ejection fraction
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Aim 1) High resolution cardiac cine imaging for global systolic function as fractional area change
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Aim 1) High resolution cardiac cine imaging for global systolic function via novel feature tracking
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Aim 1) High resolution cardiac cine imaging for global diastolic function via novel feature tracking.
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Aim 1) LV strain from magnetic resonance tissue tagging
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Aim 1) Phase contrast MRI to assess diastolic function by measurement of mitral inflow velocities.
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Aim 1) Phase contrast MRI to assess diastolic function by calculating the E/e' strain rate.
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
measure: (Sub-aim 1) End diastolic volume index (EDVi, ml/m2) in all 4 chambers
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
measure: (Sub-aim 1) End systolic volume index (ESVi, ml/m2) in all 4 chambers
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
measure: (Sub-aim 1) Stroke volume index (SVi, ml/m2, ΔSVi is the primary outcome) in all 4 chambers
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
measure: (Sub-aim 1) Ejection fraction (LVEF, %) in all 4 chambers
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
measure: (Sub-aim 1) Longitudinal strain (LS, %)
timeFrame: At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
measure: (Aim 2) TTR concentration
timeFrame: At baseline for all three cohorts
measure: (Aim 2) RBP4 concentration
timeFrame: At baseline for all three cohorts
measure: (Aim 2) Concentration of circulating misfolded TTR oligomers
timeFrame: At baseline for all three cohorts
measure: (Aim 2) TTR kinetic stability
timeFrame: At baseline for all three cohorts
Other outcomes:
measure: (Sub-aim 2) Associations between each biomarker from Aim 2 and CMRI measurements from Aim 1 and Sub-aim 1
timeFrame: At baseline for all 3 cohorts and Visit 2 for V122I TTR carriers and age-, sex-, and race-matched controls
Locations:
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Dallas
country: United States
facility: University of Texas Southwestern Medical Center
state: Texas
Study officials:
affiliation: UT Southwestern
name: Justin L Grodin, MD MPH
role: PRINCIPAL_INVESTIGATOR
References: