Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT02713880 |
| Other study ID # |
BTR 06-2018 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
August 20, 2018 |
| Est. completion date |
December 1, 2019 |
Study information
| Verified date |
February 2023 |
| Source |
CENTOGENE GmbH Rostock |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
International, multicenter, observational, longitudinal study to identify biomarker/s for the
development of a new MS-based biomarker for the early and sensitive diagnosis of
Transthyretin-Related Familial Amyloidotic Polyneuropathy from blood and number of correctly
identified patients with Transthyretin-Related Familial Amyloidotic Polyneuropathy
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.
