Phenotyping and Characterization of wtATTR-CM (TRACE 1)

Phenotyping and Characterization of Danish Wild-type Transthyretin Amyloidosis Cardiomyopathy Patients: A Cross-sectional Study

Descriptive cross-sectional study on 100 consecutive ATTRwt-CM patients reflecting all NAC stages aiming primarily to investigate ATTRwt-CM patient's quality of life (QoL) measures and their relation to ATTRwt-CM severity. Secondarily aiming to investigate the possibility to measure misTTR and fragTTR in plasma and urine and to detect fragTTR in endomyocardial biopsies from ATTRwt-CM patients. To investigate whether misTTR and fragTTR levels are correlated with ATTRwt-CM severity.

Study Overview

• Status: Recruiting
• Conditions: Quality of Life; Transthyretin Amyloidosis; Transthyretin Amyloid Cardiomyopathy; Wild-Type Transthyretin-Related (ATTR)Amyloidosis

Detailed Description

Hypothesis:

1. We hypothesize that more severe wild-type amyloidosis cardiomyopathy (ATTRwt-CM) according to clinical, biochemical, and diagnostic imaging parameters are correlated with worse quality of life (QoL) for patients.
2. We expect misfolded (misTTR) and/or fragmented transthyretin (fragTTR) to be measurable in plasma and/or urine and fragTTR to be detectable in endomyocardial biopsies from patients with ATTRwt-CM. We expect the values of misTTR and fragTTR to be correlated with the severity of ATTRwt-CM according to clinical, biochemical, and diagnostic imaging parameters. We expect the level of fragTTR from endomyocardial biopsies to be correlated with plasma levels of fragTTR.

Method:

ATTRwt-CM patients: Prospective inclusion of 100 consecutive ATTRwt-CM patients reflecting all NAC stages (40 patients from NAC disease stage 1, 40 patients from NAC disease stage II and 20 patients from NAC disease stage III). Patients will be recruited from the out-patient amyloidosis clinic at Aarhus University hospital. Patients will be thoroughly clinically assessed.

Control patients:

A control cohort of 20 age- and gender-matched heart-healthy patients will be included for comparison of total/mis-/fragTTR values.

The investigating into QoL, bio markers and the analyses on cardiac MR imaging markers will hopefully provide us with tools to evaluate and monitor disease progression and response to treatment.

• Study Type: Observational
• Enrollment (Estimated): 120

Contacts and Locations

• Study Contact: Name: Sie Kronborg Fensman, MD; Phone Number: +45 30 48 88 85; Email: siefensman@gmail.com

Study Locations

• Denmark
  • Arrhus N
    • Aarhus, Arrhus N, Denmark, 8200
      • Recruiting
      • Aarhus University Hospital
      • Contact: Sie Kronborg Fensman; Phone Number: +45 30 48 88 85; Email: siefensman@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

Including variating severity of wtATTR-CM by including 40 patients with NAC stage 1, 40 patients with NAC stage 2, and 20 patients with NAC stage 3. Furthermore, including a healthy control group in order to examine normal values of mis- and frag-TTR

Description

Group 1: wtATTR-CM patients

Inclusion Criteria:

• Patients > 18 years diagnosed with ATTRwt-CM by:
• endomyocardial biopsy
• DPD scintigraphy with Perugini grade 2-3 where variant amyloidosis is ruled out due to genetic testing.
• Informed oral and written consent

Exclusion Criteria:

• AL amyloidosis (light-chain amyloidosis).
• Myelomatosis
• Waldenström macroglobulinemia

Group 2: Control group

Inclusion Criteria:

• Patients > 18 years
• Informed oral and written consent

Exclusion Criteria:

• Known cardiovascular disease including ischemic heart disease, heart failure, atrial fibrillation, presence of a pacemaker, or malignant hypertension. Well-controlled hypertension is acceptable.
• Suspicion of cardiac amyloidosis assessed through clinical history, physical examination, ECG, and echocardiography focusing on "red flags":
• Echocardiography with:
• Myocardial hypertrophy (septum >11 mm)
• Apical sparing in LV-GLS
• Infiltrative changes in the right ventricle free wall, thickened atrioventricular valves, or thickened atrial septum
• Symptoms of polyneuropathy
• Low voltage on ECG or discrepancy between left ventricular thickness and ECG amplitude indicative of low voltage
• Atrioventricular block (AV block)
• Bilateral carpal tunnel syndrome
• Surgery for spinal stenosis
• Elevated troponin I or NT-pro-BNP

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort
wtATTR-CM patients (n = 100); Clinical history, physical examination, ECG, advanced echocardiography, blood and urine samples, cardiac magnetic resonance imaging (CMRI), and QoL questionaires (KCCQ, EQ-5Q-5L and ATTR-QoL)). Subgroup with these patient (n = 10): A endomyocardial biopsy.
Control (n = 20); Blood and urine samples. To rule out cardiac disease: clinical history, physical examination, ECG and advanced echocardiography.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Investigation of cardiac amyloidosis severity in patients with Wild-type Transthyretin Amyloidosis Cardiomyopathy.	Amyloid severity will be addressed using primarily NAC-stages and NYHA-class. Furthermore, we will use NT-pro-BNP, findings on echo (stroke volume, ejectionfraction and global longitudional strain) and finding on CMRI (LV mass, T1 myocardial values and extracellular volume).	Through study completion, 2 years.
Investigation of the relations between cardiac amyloid severity and patient quality of life in patients with Wild-type Transthyretin Amyloidosis Cardiomyopathy.	Quality of life will be addressed using KCCQ summary score, EQ-5D Utility score and VAS ranging score and ATTR-QOL total score.	Through study completion, 2 years.
Assessment of transthyretin and pathogenic fragments and relation to cardiac amyloid severity in patients with Wild-type Transthyretin Amyloidosis Cardiomyopathy	Transthyretin (TTR) will be measured as follows: total TTR, misfolded TTR and fragmented TTR in plasma and misfolded TTR and fragmented TTR in urine.	Through study completion, 2 years.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Validation of a new amyloid specific questionnaire (ATTR-QoL) in comparison with Kansas City Cardiomyopathy Questionnaire (KCCQ)	Comparing ATTR-QOL total score to KCCQ summary score and EQ-5D Utility score and VAS ranging score.	Through study completion, 2 years.

Collaborators and Investigators

• Sponsor: Steen Hvitfeldt Poulsen
• Collaborators: Novo Nordisk A/S

Study record dates

Study Major Dates

• Study Start (Actual): February 20, 2024
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: January 30, 2024
• First Submitted That Met QC Criteria: February 26, 2024
• First Posted (Actual): March 4, 2024

Study Record Updates

• Last Update Posted (Estimated): August 15, 2025
• Last Update Submitted That Met QC Criteria: August 12, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Cardiovascular Diseases; Heart Diseases; Neuromuscular Diseases; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Peripheral Nervous System Diseases; Neurodegenerative Diseases; Heredodegenerative Disorders, Nervous System; Proteostasis Deficiencies; Amyloid Neuropathies; Amyloidosis, Familial; Cardiomyopathies; Amyloidosis; Amyloid Neuropathies, Familial
• Other Study ID Numbers: 1-10-72-189-23

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
• product manufactured in and exported from the U.S.: No