Trial document




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  DRKS00016158

Trial Description

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Title

TTR Screening - Screening for Hereditary Transthyretin Related Amyloidosis - an International, Multicentre, Epidemiological Protocol

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Trial Acronym

TRAM2 analyse Project

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URL of the Trial

https://www.centogene.com/science/research-projects/ttr-tram.html

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Brief Summary in Lay Language

Estimation of the prevalence of TTR in patients with polyneuropathy or cardiomyopathy undetermined etiology

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Brief Summary in Scientific Language

Transthyretin (TTR) amyloidosis (A-TTR) is a rare protein misfolding, autosomal dominant inherited disease with variable penetrance. It presents with a wide spectrum of clinical manifestations. TTR, the protein implicated in A-TTR, is a tetrameric transport protein.
Misfolded TTR protein forms amyloid fibrils causing tissue damage by direct compression and obstruction. In the earliest stages of the disease the symptoms comprise autonomic and/or sensory symptoms. The clinical spectrum of A-TTR (Amyloidosis TTR) varies widely from an exclusive neurological involvement to a predominant cardiac presentation. In the first case, the disease is called TTR familial amyloid polyneuropathy (TTR-FAP). In the second case, the disease is called TTR amyloid cardiomyopathy (TTR-CM). Most likely this classification does not really make sense further on, since the clinical picture is in the majority of the patients (>62%) overlapping. TTR-FAP is a fatal illness resulting from autosomal dominantly inherited single-point mutations on the TTR gene. This disease typically strikes people in their 30s to 50s. TTR-CM may occur alone or in conjunction with TTR-FAP. TTR-CM is often associated with genetic variants of TTR but may also occur in the absence of a specific mutation, what is known as wild-type A-TTR (A-TTRwt). A-TTR is probably widely underdiagnosed, mainly because the disease can mimic other causes of left ventricular (LV) hypertrophy (LVH), including hypertensive heart disease and hypertrophic cardiomyopathy (HCM). In an adult, HCM is defined by the presence of a LV wall thickness ≥15 mm in one or more LV myocardial segments that is not explained solely by abnormal loading conditions. Five to ten percent of adult cases are caused by genetic disorders including inherited metabolic and neuromuscular diseases, chromosome abnormalities and genetic syndromes. Some patients have non-genetic disorders that mimic genetic forms of the disease, for example, senile A-TTR (which is an A-TTRwt) and light chain amyloidosis (AL).The diagnosis of HCM is based on the detection of increased LV wall thickness by any imaging modality. Cardiac amyloidosis (CA) is a manifestation of several systemic diseases known as amyloidosis. Clinical features are varied, and although heart failure symptoms predominate, suspicion of CA can also be prompted by syncope, arrhythmias, or unexplained LV wall thickening on echocardiography (ECHO). The three most frequent and clinically challenging types of systemic amyloidosis are acquired monoclonal immunoglobulin light chain amyloidosis (AL), the hereditary mutant A-TTR (A-TTRm), and the non-mutant A-TTR, also known as systemic "senile" amyloidosis or A-TTRwt (TTR wild type Amyloidosis). AL and A-TTRm can affect the heart in isolation or with multiorgan involvement, whereas A-TTRwt predominantly affects the heart and the carpal tunnel ligament. The diagnosis of TTR-CM remains challenging. The electrocardiograms (ECGs), transthoracic ECHO (TTE) and cardiac magnetic resonance (CMR) of TTR-CM show similar findings to cardiac AL. The diagnosis strategy for A-TTR combines pathology and molecular genetic testing. TTR is a gene of small size (7 kB), including four exons, and its screening by full sequencing of the coding parts is now easily accessible. In asymptomatic A-TTR carriers, CMR may detect early cardiac involvement by focal myocardial late gadolinium enhancement (LGE). Routine laboratory testings' are helpful. High levels of brain natriuretic peptide (BNP), N-terminal pro-brain natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) are associated with cardiovascular events, heart failure and death. Despite comparable values of LV wall thickness, plasma BNP values are three to five folds higher in patients with TTR-CM than in patients with other causes of HCM.

Non-invasive techniques have been developed in the last years to assist in the diagnosis of TTR-CM, One of the imaging techniques is the bone scintigraphy that has been shown to have excellent results in the diagnosis of TTR-CM. Several studies have suggested that TTR-derived fibrils show avidity for bone tracers, in particular 99m Technetium-3,3-diphosphono-1,2-propano-di-carboxylic acid (99mTc-DPD). For this reason, 99mTc-DPD scintigraphy should be considered in patients in whom TTR-CM is suspected, supporting the diagnosis when histology is not or hardly achievable. The TTR-FAP has a very heterogeneous phenotype which can manifest starting at the age of 18 and may lead to death within 10 years. The symptoms can be categorized in three groups:

Dysfunction of peripheral nerves:

- Dissociated anesthesia

- Muscle paresis and atrophy

- Dysaesthesia and paraesthesia

- Reduced skin temperature

- Coldness

- Hoarseness

Autonomic dysfunction:

- Dysuria

- Diarrhea

- Constipation

- Orthostatic dysregulation

- Erectile dysfunction

- Nausea

Constitutional conditions

- Anemia

- Weight loss

- Arrhythmia

- Edema

- Acroparaesthesia

The currently available therapeutic approaches are either liver transplantation (as the liver mainly produces transthyretin this is a feasible approach) or as of more recently also a TTR-tetramer stabilizing agent (Tafamidis). Tafamidis (Vyndaqel®) gained the European approval under "exceptional circumstances" in November 2011 for treating FAP in adults with a symptomatic polyneuropathy. Further products are actually under development and in market access stages.

In light of the different potential therapies being available in the market this analysis aims to determine the frequency of TTR based hereditary transthyretin-related amyloidosis in a selected, clinical subpopulation.

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Organizational Data

  •   DRKS00016158
  •   2019/03/12
  •   2017/07/31
  •   no
  •   Approved
  •   A2018-0069, Ethik-Kommission an der Medizinischen Fakultät der Universität Rostock
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Secondary IDs

  •   NCT03237494  (ClinicalTrials.gov)
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Health Condition or Problem studied

  •   G60-G64 -  Polyneuropathies and other disorders of the peripheral nervous system
  •   I42 -  Cardiomyopathy
  •   E85 -  Amyloidosis
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Interventions/Observational Groups

  •   NGS-based sequencing of the TTR gene is performed in all patients with an unclear diagnosis of polyneuropathy / unclear cardiomyopathy for the molecular genetic diagnosis of the TTR disease. Dried blood drops are used for this procedure. This is a one-time examination.
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Characteristics

  •   Non-interventional
  •   Epidemiological study
  •   Other
  •   Open (masking not used)
  •   [---]*
  •   Other
  •   Diagnostic
  •   Other
  •   N/A
  •   N/A
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Primary Outcome

- Estimation of the prevalence of TTR in patients with polyneuropathy or cardiomyopathy of undetermined etiology; time frame: 24 months; evaluate the number of patients with the TTR disease

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Secondary Outcome

- Number of correctly identified patients with hereditary transthyretin-related amyloidosis; time frame: 24 months; we evaluate which symptoms frequently occur. we measured by the evaluation of the eCRF.

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Countries of Recruitment

  •   Germany
  •   Austria
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Locations of Recruitment

  •  
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • Doctor's Practice 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • University Medical Center 
  • Medical Center 
  • Medical Center 
  • Medical Center 
  • Doctor's Practice 
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Recruitment

  •   Actual
  •   2017/07/31
  •   5000
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   75   Years
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Additional Inclusion Criteria

- Informed consent will be obtained from the patient before any study related
procedures.

- Patients with cardiomyopathy or polyneuropathy of undetermined etiology the latter one based on the normal results of laboratory data

- Patients aged between 18 and 75 years

- No anamnesis for carcinoma,

- No continuous alcohol consumption

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Exclusion Criteria

- No Informed consent from the patient any study related procedures.

- Patient younger than 18 years or older than 75 years

- The etiology of the cardiomyopathy or polyneuropathy is already known

- Pos. anamnesis for carcinoma,

- Continuous alcohol consumption

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Addresses

  • start of 1:1-Block address primary-sponsor
    • Centogene AG Rostock
    • Mr.  Dr.  Anton  Mamin 
    • Am Strande 7
    • 18055  Rostock
    • Germany
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    • Centogene AG Rostock
    • Mr.  Dr.  Anton  Mamin 
    • Am Strande 7
    • 18055  Rostock
    • Germany
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    • Centogene AG
    • Ms.  Susanne  Zielke 
    • Am Strande 7
    • 18055  Rostock
    • Germany
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Sources of Monetary or Material Support

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    • Centogene AG
    • Mr.  Dr  Anton  Mamin 
    • Am Strande 7
    • 18055  Rostock
    • Germany
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Status

  •   Recruiting ongoing
  •   [---]*
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Trial Publications, Results and other Documents

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