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Hereditary Transthyretin-Related Amyloidosis and Longitudinal Monitoring of TTR Positive Subjects (TRAMmoniTTR)

In cooperation with Alnylam® Pharmaceuticals

The genetic screening of an at-risk population for hereditary TransthyRetin-related AMyloidosis and longitudinal monitoring of TTR positive subjects, the TRAMmoniTTR study, is a multicenter, observational, epidemiological, longitudinal study.

Summary

Overview

The TRAMmoniTTR study aims to investigate the ATTRv prevalence in an at-risk population, monitor clinical status in TTR positive subject, and establish ATTRv biomarker(s). 

Hereditary Transthyretin Amyloidosis is an autosomal dominant condition caused by a pathogenic variant in the TTR gene (Plante-Bordeneuve et al. 2011), also known as ATTRv (hereditary amyloidosis transthyretin variant). The TTR gene is coding for transthyretin protein (Ttr), formerly known as prealbumin. Transthyretin is found primarily in the serum (secreted by the liver) and cerebrospinal fluid (secreted by the choroid plexus), and functions as a carrier, *trans*port for the hormone *thyr*oxine (T4) and *retin*ol-binding protein (bound to retinol or vitamin A). The destabilization of the Ttr protein and the formation of misfolded Ttr proteins results in the transthyretin amyloidosis diseases.

On average, the diagnosis is delayed by 4–5 years, especially in non-endemic areas. Also, potential misdiagnosis is due to ATTRv´s clinical heterogeneity (Adams et al., 2016).

Patient Benefits

Participants will receive a definite diagnosis if a pathogenic variant in the TTR gene is found.

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Study access on CentoPortal® for participating physicians

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Study Rationale & Design

Study Rationale

Hereditary Transthyretin Amyloidosis (ATTRv, hereditary amyloidosis, transthyretin-related) is an autosomal dominant condition caused by a pathogenic variant in the TTR gene (Plante-Bordeneuve et al. 2011). The TTR gene is coding for transthyretin, formerly known as prealbumin. Transthyretin (TTR) is found primarily in the serum (secreted by the liver) and cerebrospinal fluid (secreted by the choroid plexus), and functions as a carrier for the hormone thyroxine (T4) and retinol-binding protein (bound to retinol or vitamin A). The destabilization of the TTR protein and the formation of misfolded Ttr proteins results in the transthyretin amyloidosis (ATTRv) diseases.

On average, the diagnosis is delayed by 4–5 years, especially in non-endemic areas. Also, potential misdiagnosis is due to ATTRv´s clinical heterogeneity (Adams et al., 2016).

In order to facilitate early diagnosis, treatment choice, and individualization, ATTRv biomarker(s) are crucial.

Study Design

The patients fulfilling the inclusion criteria will be enrolled into the Study. All participants will have a single research blood sample drawn, which will be equivalent to 30 drops of blood (around 1ml). The sample will be applied to a CentoCard®, which will be sent to CENTOGENE and analyzed in CENTOGENE’s laboratory.

The sample will be molecular genetically tested with NGS-based sequencing of the entire TTR gene.

QUARTERLY VISITS TIME BLOOD COLLECTION eCRF
V1 0 months yes yes
V2 3 months yes yes
V3 6 months yes yes
V4 9 months yes yes
V5 12 months yes yes
V6 15 months yes yes
V7 18 months yes yes
V8 21 months yes yes
V9 24 months yes yes

TRAM STUDY RESULTS PUBLICATION: ANNALS OF MEDICINE; 53:1, 1787-1796. PUBLISHED 2021 OCT 16.

Information About the Study

Design: Epidemiological, multicenter, international, and non-interventional study

Study population: Participants at risk for Hereditary Transthyretin Amyloidosis (hATTR) and participants diagnosed with hATTR

Number of patients: 5,000 participants

First patient in: April 2018

End of study: April 2024

Objectives:

  • To monitor clinical status in TTR positive subjects
  • To investigate the hATTR prevalence in an at-risk population
  • To establish hATTR biomarker/s

Find out how you can participate: ClinicalTrials.gov

Inclusion Criteria

Inclusion Criteria
Informed consent is obtained from the participant
The participant is 18 years of age or older
The participant has no diagnosis of alcoholism according to international guidelines
The participant has not undergone chemotherapy for any carcinoma

The participant is at risk for ATTRv due to two or more the factors listed below:

  • Cardiomyopathy or polyneuropathy with no obvious etiology
  • Atypical Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) or Motor Neuron Disease (MND)
  • Autonomic dysfunction
  • Hypertrophic cardiomyopathy or heart failure with preserved ejection fraction Left Ventricular Hypertrophy (LVH)
  • Bilateral carpal tunnel syndrome
  • Spinal stenosis or spinal radiculopathy
  • Gait disorders
  • Ocular changes involving vitreous opacities
  • Unexplained weight loss >5kg
  • Renal abnormalities
  • Family history of ATTRv
  • Based on imaging or biopsy suspected for the wild type TTR (ATTR) and not genetically tested for ATTRv
OR
  • The participant is diagnosed with ATTRv
OR
  • The participant is a first or second degree relative of the TTR positive subject

Contact TRAMmoniTTR Study

Scientific Advisory Board (SAB)

PD Dr. Katrin Hahn (Chairwoman)
Universitätsmedizin Charité
10117  Berlin
Germany
Email: Katrin.Hahn(at)charite(dot)de


Prof. Dr. Birgit Aßmus
UKGM Giessen
35385 Giessen
Germany
Email: birgit.assmus(at)innere.med.uni-giessen(dot)de


Prof. Dr. Thomas Skripuletz
Medizinische Hochschule Hannover
30625 Hannover
Germany
Email: Skripuletz.Thomas(at)mh-hannover(dot)de


Prof. Dr. Monika Patten-Hamel
UKE Hamburg
20246 Hamburg
Germany
Email: patten(at)uke(dot)de


Prof. Dr. Peter Bauer
CENTOGENE GmbH
Am Strande 7
18055 Rostock
Germany
Email: peter.bauer(at)centogene(dot)com

Project Team – CENTOGENE

Sabine Rösner
Clinical Project Manager
CENTOGENE GmbH
Am Strande 7
18055 Rostock
Germany
Email: sabine.roesner(at)centogene(dot)com


Dr. Xenia Bogdanovic
Clinical Study Researcher
CENTOGENE GmbH
Am Strande 7
18055 Rostock
Germany
Email: dr.xenia.bogdanovic(at)centogene(dot)com


Felix Reder
CPM Team Leader
CENTOGENE GmbH
Am Strande 7
18055 Rostock
Germany
Email: felix.reder(at)centogene(dot)com