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Trial record 13 of 365 for:    transthyretin

Screening for the Transthyretin-Related Familial Amyloidotic Small Fiber Polyneuropathy (TRAP2.1) (TRAP2-1)

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ClinicalTrials.gov Identifier: NCT01705626
Recruitment Status : Recruiting
First Posted : October 12, 2012
Last Update Posted : July 12, 2019
Sponsor:
Information provided by (Responsible Party):
Centogene AG Rostock

Tracking Information
First Submitted Date October 9, 2012
First Posted Date October 12, 2012
Last Update Posted Date July 12, 2019
Study Start Date December 2016
Estimated Primary Completion Date February 28, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures Not Provided
Original Primary Outcome Measures Not Provided
Change History Complete list of historical versions of study NCT01705626 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Screening for the Transthyretin-Related Familial Amyloidotic Small Fiber Polyneuropathy (TRAP2.1)
Official Title TTR-FAP Screening - Screening for the Transthyretin-Related Familial Amyloidotic Small Fiber Polyneuropathy - a International, Multicentre, Epidemiological Protocol
Brief Summary The goal of this study is to investigate the prevalence of Transthyretin-Related Familial Amyloidotic Polyneuropathy (TTR-FAP) in a cohort of 500 subjects at risk for TTR-FAP, based on the subject's clinical presentation.
Detailed Description

Conformational changes in human proteins can induce several types of diseases. The nature of the conformational changes is unknown, but some lead to amyloid fibril formation, which accumulate in the extra-cellular space of tissues and result in disruption of organ function. Amyloidosis is a group of diseases in which normally soluble proteins undergo a conformational change and aggregate into amyloid fibrils. Amyloid diseases belong to a broader defined group, called protein-aggregation diseases. This group also includes disorders characterized by intracellular amyloid-like aggregates, with Huntington's and Parkinson's diseases and familial amyotrophic lateral sclerosis being the most well known.

Familial amyloid polyneuropathy (FAP) associated with mutations in the transthyretin (TTR) gene is the most common form of genetic amyloidosis. It accounts several thousand cases worldwide, with Val30Met mutation identified in most patients and with endemic foci in Portugal, Sweden and Japan.

Also known as Corino de Andrade's disease, Transthyretin-related Familial Amyloid Polyneuropathy (TTR-FAP) is an autosomal dominant, progressive neurodegenerative disease with fatal outcome occurring within ten years after onset., caused by the systemic deposition of amyloidogenic variants of the transthyretin protein (TTR). It is TTR's dissociation, misfolding and aggregation that leads to the degeneration of post-mitotic tissue and, eventually, to the amyloid disease. The amyloid deposits are found especially in the peripheral nervous system, leading to a progressive sensory and motor polyneuropathy.

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). It is also called 'prealbumin' or 'thyroxine-binding prealbumin' (TBPA), due to it runs faster than albumin on the electrophoresis gel. This homo-tetrameric plasma protein may aggregate and form the fibrillar material associated with TTR amyloidosis. Dissociation of the TTR tetramer seems to occur prior to fibril formation, and therefore, studies aiming at the discovery of compounds that stabilize the protein's quaternary structure, thereby acting as amyloid inhibitors, are being performed.

The TTR gene is found on the long arm (q) of chromosome 18 in the region 18q11.2-q12.1 and consists of four exons and three introns spanning about 7 kbp (Tsuzuki et al., 1985). More than 120 single TTR mutations have been identified and most of them are known to cause disease (Sekijima et al., 1993-2016). The most common mutation in TTR-FAP is a replacement of valine by methionine (TTR V30M). The single mutations associated with FAP point to a destabilization of TTR, accelerating the dissociation of the folded tetramer into monomeric amyloidogenic intermediates (Damas et al., 1996; Quintas et al., 1999; Hammarstrom et al., 2002). In vitro studies have recently shown that binding of the natural ligand T4 to the TTR central hydrophobic channel stabilizes the tetramer and consequently reduces amyloid fibril formation.

The typical presentation of TTR-FAP is a progressive sensory-motor polyneuropathy, which usually begins with loss of thermal and pain sensation in the feet, slowly ascends up the limbs and is associated with variable autonomic disturbances and extra-neurological manifestations (especially a cardiomyopathy). Liver and heart failure mark the terminal state of the disease, while initial symptoms are indicative of motor (distal weakness), sensory (paraesthesias, numbness, distal burning, pain) and autonomic (impotence, diarrhea, persistent constipation, symptoms of gastric and bladder paresis, orthostatic hypotension, syncope, abnormal sweating) dysfunction.

Some patients with an early-onset presentation deteriorate quickly because of autonomic dysfunction and rapid progression of the sensory-motor deficit. Diagnosis is based on family history, neurographic evidence of a prevalent axonal polyneuropathy, identification of amyloid deposits in the tissues, and detection of TTR mutation. Common misdiagnosis: chronic inflammatory demyelinating polyneuropathy (CIDP), coincidental diabetes mellitus or monoclonal gammapathy.

It is the goal of this study to investigate the prevalence of Transthyretin-Related Familial Amyloidotic Polyneuropathy (TTR-FAP) in a cohort of 500 subjects at risk for TTR-FAP, based on the subject's clinical presentation. All newly identified patients will be given the opportunity to participate in one of the Biomarker studies conducted by CENTOGENE, called BioTRAP, to further detect and validate new biomarkers for TTR-FAP.

Study Type Observational
Study Design Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration Not Provided
Biospecimen Retention:   Samples With DNA
Description:
For the molecular genetic diagnosis of the disease TTR-FAP a sequencing of the entire TTR gene in all study patients will be performed. Dried blood spots will be used for this procedure.
Sampling Method Probability Sample
Study Population Adult patients with small fiber polyneuropathy of undetermined etiology.
Condition
  • Transthyretin Amyloidosis
  • Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy
  • Polyneuropathies
Intervention Not Provided
Study Groups/Cohorts Observation
All adult patients older than 18 years with small fiber polyneuropathy of undetermined etiology.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Recruiting
Estimated Enrollment
 (submitted: October¬†11,¬†2012)
500
Original Estimated Enrollment Same as current
Estimated Study Completion Date April 30, 2020
Estimated Primary Completion Date February 28, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

  • Informed consent is obtained from the participant
  • The participant is aged between 18 and 85 years of age
  • The participant is diagnosed with small fiber polyneuropathy of no obvious etiology
  • The participant has no diagnosis of alcoholism, according to International Guidelines
  • The participant has not undergone chemotherapy for carcinoma

Exclusion Criteria:

  • Inability to provide informed consent
  • The participant is younger than 18 years or older than 85 years of age
  • The etiology of the small fiber polyneuropathy is clearly determined
  • The participant has a diagnosis of alcoholism, according to International Guidelines
  • The participant has undergone chemotherapy for carcinoma
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers No
Contacts
Contact: Volha Skrahina, Dr +4938180113594 ext 594 volha.skrahina@centogene.com
Listed Location Countries Austria,   Hungary,   Poland,   Serbia,   Spain
Removed Location Countries Germany
 
Administrative Information
NCT Number NCT01705626
Other Study ID Numbers TRAP 08-2012
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement
Plan to Share IPD: Undecided
Responsible Party Centogene AG Rostock
Study Sponsor Centogene AG Rostock
Collaborators Not Provided
Investigators
Principal Investigator: Arndt Rolfs, MD Centogene AG Rostock
PRS Account Centogene AG Rostock
Verification Date July 2019