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Biomarker for Transthyretin-Related Familial Amyloidotic Polyneuropathy (BioTRAP) (BioTRAP)

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ClinicalTrials.gov Identifier: NCT02713880
Recruitment Status : Recruiting
First Posted : March 21, 2016
Last Update Posted : September 17, 2019
Sponsor:
Information provided by (Responsible Party):
Centogene AG Rostock

Brief Summary:
Development of a new MS-based biomarker for the early and sensitive diagnosis of Transthyretin-Related Familial Amyloidotic Polyneuropathy from blood

Condition or disease
Transthyretin Amyloidosis Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy Transthyretin Amyloid Cardiopathy

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Detailed Description:

Diseases of diverse etiology can be correlated to the term "polyneuropathy"(PNP). The pathogenesis may be of inflammatory, autoimmune, metabolic, toxic or hereditary nature. Careful clinical and electrodiagnostic assessment, with attention to the pattern of involvement and the types of nerve fibers most affected, narrows the differential diagnosis and helps to focus the laboratory evaluation. Beside the frequent genetic etiologies in PNP (pmp22, MFN2) one cause of a polyneuropathy may be a hereditary amyloidosis. This term describes the accumulation of misfolded protein in the interstitial space. The abnormal accumulation of β-fibrils can be detected histologically by Congo pink staining. Aside from acquired amyloidotic neuropathies (e.g. PNP caused by AL-amyloidosis [AL= amyloidosis with light chain immunoglobins]) there are also hereditary amyloidotic neuropathies.

These have been described as endemic in Sweden, Portugal or Japan. More recent studies provided evidence for the presence of hereditary amyloidotic neuropathies amongst the German population and that they are currently underdiagnosed. The most common form of the hereditary familial amyloidotic neuropathy (FAP) is the Transthyretin-related FAP, however two other amyloidogenic proteins have been described: Apolipoprotein A-I and Gelsolin (Ando et al., 2005; Adams et al., 2010).

The TTR-FAP is an autosomal dominant disease, the exact prevalence of which is unknown but estimated to be around 1:100,000 to 1:1,000,000 in the normal population. By limiting the study population to patients with PNP of unknown etiology it should be possible to gain evidence for the prevalence of the disease in Germany by investigating fewer patients.

While the diagnosis of the amyloidotic neuropathy can be conducted histologically, a molecular genetic approach is necessary to diagnose TTR-FAP. Even though more than 100 point mutations are known to cause the disease, the most common amino acid change is V30M.

The mutation in the TTR gene causes the destabilization of the physiologically tetrameric protein. Usually transthyretin consists of four identical monomeric subunits and binds the thyroxin circulating in the blood plasma. The monomeric subunits exhibit a pronounced β- sheet structure which leads to the accumulation of unsoluble β-fibrils when they are destabilised as in TTR-FAP.

This accumulation of misfolded TTR can lead to three phenotypes known as:

  • cardiac TTR amyloidosis
  • leptomeningeal TTR amyloidosis and the
  • TTR-FAP

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 (Ando et al. 2005):

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. In light of the potential therapy of this very rare disease, this study aims to determine the prevalence of TTR-FAP in a selected, clinical subpopulation. New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood (plasma) of affected patients that allow diagnosing in the future the disease earlier, with a higher sensitivity and specificity.

Therefore it is the goal of the study to identify and validate a new biochemical marker from the plasma of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment.


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Study Type : Observational
Estimated Enrollment : 1000 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Biomarker for Transthyretin-Related Familial Amyloidotic Polyneuropathy - An International, Multicenter, Epidemiological Protocol
Actual Study Start Date : August 20, 2018
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021


Group/Cohort
Observation
Patients with Transthyretin-Related Familial Amyloidotic Polyneuropathy or high-grade suspicion for Transthyretin-Related Familial Amyloidotic Polyneuropathy



Primary Outcome Measures :
  1. Development of a new MS-based biomarker for the early and sensitive diagnosis of Transthyretin-Related Familial Amyloidotic Polyneuropathy from blood [ Time Frame: 24 months ]
    New methods, like mass-spectrometry give a good chance to characterize specific metabolic alterations in the blood of affected patients that allow diagnosing in the future the disease earlier, with a higher sensitivity and specificity.


Secondary Outcome Measures :
  1. Number of correctly identified patients with Transthyretin-Related Familial Amyloidotic Polyneuropathy [ Time Frame: 36 months ]
    the goal of the study to identify and validate a new biochemical marker from the blood of the affected patients helping to benefit other patients by an early diagnose and thereby with an earlier treatment.


Biospecimen Retention:   Samples With DNA
For the development of the new biomarkers using the technique of Mass-spectometry, maximal 7,5 blood will be taken from the patient via a dry blood spot filter card. To proof the correct diagnosis in those patients where up to the enrolment in the study no genetic testing has been done, sequencing will be done. The analyses will be done at the Centogene AG Am Strande 7 18055 Rostock Germany


Information from the National Library of Medicine

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Ages Eligible for Study:   2 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population
Patients with Transthyretin-Related Familial Amyloidotic Polyneuropathy or high-grade suspicion for Transthyretin-Related Familial Amyloidotic Polyneuropathy
Criteria

Inclusion Criteria:

  • Informed consent will be obtained from the parents before any study related procedures.
  • Patients of both genders older than 2 months
  • The patient has a diagnosis of Transthyretin-Related Familial Amyloidotic Polyneuropathy or a high-grade suspicion for Transthyretin-Related Familial Amyloidotic Polyneuropathy
  • High-grade suspicion present, if one or more inclusion criteria are valid:

    • Positive family anamnesis for Transthyretin-Related Familial Amyloidotic -Polyneuropathy
    • Orthostatic dysregulation
    • Acroparaesthesia
    • Dysaesthesia and paraesthesia
    • Muscle paresis and atrophy

Exclusion Criteria:

  • No Informed consent from the parents before any study related procedures.
  • Patients of both genders younger than 2 months
  • No diagnosis of Transthyretin-Related Familial Amyloidotic Polyneuropathy or no valid criteria for profound suspicion of Transthyretin-Related Familial Amyloidotic Polyneuropathy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02713880


Contacts
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Contact: Volha Skrahina, Dr +4938180113594 ext 594 volha.skrahina@centogene.com

Locations
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Germany
Centogene AG Active, not recruiting
Rostock, Germany, 18055
India
Navi Mumbai Institute of Research In Mental And Neurological Handicap (NIRMAN) Recruiting
Mumbai, India, 400705
Contact: Anil Jalan, Dr.         
Sponsors and Collaborators
Centogene AG Rostock
Investigators
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Principal Investigator: Arndt Rolfs, Prof. Centogene AG Rostock

Additional Information:
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Responsible Party: Centogene AG Rostock
ClinicalTrials.gov Identifier: NCT02713880     History of Changes
Other Study ID Numbers: BTR 06-2018
First Posted: March 21, 2016    Key Record Dates
Last Update Posted: September 17, 2019
Last Verified: March 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Centogene AG Rostock:
Amyloid Neuropathies
Biomarker
Additional relevant MeSH terms:
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Polyneuropathies
Amyloid Neuropathies
Amyloid Neuropathies, Familial
Amyloidosis
Proteostasis Deficiencies
Metabolic Diseases
Peripheral Nervous System Diseases
Neuromuscular Diseases
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Amyloidosis, Familial
Metabolism, Inborn Errors