Subclinical Transthyretin Cardiac Amyloidosis in V122I TTR Carriers

Amyloidosis Cardiac Clinical Trial

Official title:

Identifying Subclinical Transthyretin Cardiac Amyloidosis in Asymptomatic Carriers of the V122I TTR Allele

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05489549
• Other study ID #: STU-2022-0404
• Secondary ID: 1R01HL160892-01A
• Status: Recruiting
• Start date: November 21, 2022
• Est. completion date: June 30, 2027

Study information

• Verified date: May 2024
• Source: University of Texas Southwestern Medical Center
• Contact: Amy Browning
• Phone: 214-645-8040
• Email: Amy.Browning[@]utsouthwestern.edu
• Is FDA regulated: No
• Study type: Observational

Clinical 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. 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 500
• Est. completion date: June 30, 2027
• Est. primary completion date: June 30, 2027
• Gender: All
• Age group: 30 Years to 80 Years

Eligibility

(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

Related Conditions & MeSH terms

• Amyloidosis
• Amyloidosis Cardiac
• Amyloidosis, Familial
• Amyloidosis, Hereditary
• Cardiomyopathies
• Transthyretin-Related (ATTR) Familial Amyloid Cardiomyopathy

Locations

Country	Name	City	State
United States	Cleveland Clinic	Cleveland	Ohio
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Columbia University Medical Center	New York	New York

Sponsors (5)

Lead Sponsor	Collaborator
University of Texas Southwestern Medical Center	Columbia University, National Heart, Lung, and Blood Institute (NHLBI), The Cleveland Clinic, The University of Texas at Arlington

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	(Sub-aim 2) Associations between each biomarker from Aim 2 and CMRI measurements from Aim 1 and Sub-aim 1	To achieve this, we will employ multivariable generalized linear mixed models to determine the independent association between these biomarkers and CMRI measurements in V122I TTR carriers without HF. Additionally, after determining the univariable association between each biomarker and outcome from Aim 1 and Sub-aim 1, we will employ a backwards selection algorithm from a list of confounders (eGFR, sex, age, hypertension, and BMI) and each biomarker to determine the biomarker(s) most closely associated with subclinical hATTR-CA.	At baseline for all 3 cohorts and Visit 2 for V122I TTR carriers and age-, sex-, and race-matched controls
Primary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Primary	(Sub-aim 1) ? stroke volume index (?SVi)	We will measure and compare ?SVi (%) 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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls)
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
Secondary	(Sub-aim 1) Stroke volume index (SVi, ml/m2, ?SVi 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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
Secondary	(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.	At baseline (for V122I TTR carriers and age-, sex-, and race-matched controls) enrolled at UT Southwestern
Secondary	(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.	At baseline for all three cohorts
Secondary	(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.	At baseline for all three cohorts
Secondary	(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.	At baseline for all three cohorts
Secondary	(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.	At baseline for all three cohorts