Early Diagnosis of TTR Amyloidosis by Use of Molecular Biology (ADDITION)

December 7, 2022 updated by: Assistance Publique - Hôpitaux de Paris

Project to Accelerate the Diagnosis of TTR Amyloidosis by Use of Molecular Biology in First Intention

Peripheral neuropathies are diseases that affect the nervous system outside the brain and spinal cord, their prevalence is 1% in the general population, the causes are extremely varied with more than 200 identified causes; the main ones are diabetes, excessive alcohol consumption and chemotherapy. They may be sometimes disabling but generally preserve autonomy.

Transthyretin amyloidosis is a rare multisystematic hereditary disease with autosomal dominant transmission. They present usually as a peripheral neuropathies (FAP). They are due to a point mutation of the transthyretin gene (chr 18q). FAP is secondary to endoneurial amyloid deposits and are characterized by a slowly progressive sensory, motor and autonomic. FAP is the most severe hereditary polyneuropathy of the adult are irreversible and fatal within 5 to 12 years from onset.

Most frequent mutation of TTR gene is located on the second exon; but more than 100 mutations have been reported.

Prevalence of FAP is 1 per 1 million inhabitants. They have been reported until 1990s' in four endemic areas North of Portugal, Sweden, Japan and Majorca. In these areas, diagnosis is facilitated because of the stereotypical presentation : a length-dependent polyneuropathy with predominant involvement of thermal and pain sensations and autonomic dysfunction, early onset in the third decade and a predominant Met30 TTR mutation. Positive family history is frequent 85% (one of the parents is affected). Diagnosis requires detection of TTR mutation by molecular biology (blood sample) and characterization of amyloid deposit on labial salivary gland biopsy.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Detailed Description

Study of the TTR gene by complete sequencing; search for amyloidogenic mutations of the TTR gene (according to the site http: // amyloidosismutations.com / mut-attr.php) in the laboratory of molecular biology of the CHU BICÊTRE (APHP) managed by Pr Anne Mantel.

Preselection of the cases to be tested among the cases of peripheral neuropathies of indetermined cause referred via the network Cornamyl of which the reference centers of the neuromuscular diseases are belonging .

Currently, FAP is a worldwide disease. Diagnosis of TTR-FAP is extremely difficult and usually delayed by 4 years in non endemic areas for many reasons :

  • positive family history are lacking in 50% of cases (sporadic forms).
  • incomplete ability of biopsies to characterize amyloid deposits.
  • clinical presentation is varied and may mimick many types of rare peripheral neuropathies: CIDP, axonal idiopathic polyneuropathy, upper limb neuropathies, recurrent carpal tunnel syndrome after surgery, ataxic neuropathy, motor neuropathy.

Conversely to endemic areas, look for V30M mutation is not enough to exclude TTR-FAP, TTR gene sequencing is required.

With the help of the french network for FAP (Cornamyl), cases have been identified in 81/100 geographical departments, with a wide genetic heterogeneity (41 mutations reported) ; age of onset is late: 75% after 50 yo.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
560

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Grenoble, France, 38043
        • CHU Grenoble
      • Lille, France, 59037
        • CHRU LILLE
      • Limoges, France, 87042
        • CHU Dupuytren
      • Marseille, France, 13000
        • CHU La Timone
      • Montpellier, France, 34295
        • Hopital guy-de-Chauliac
      • Paris, France, 75013
        • Hôpital de la Salpêtrière
      • Strasbourg, France, 67098
        • Hôpital de Hautepierre
    • Kremlin Bicetre
      • Le Kremlin Bicetre, Kremlin Bicetre, France, 94270
        • CHU Bicetre
    • Martinique
      • Martigues, Martinique, France, 97200
        • CHU Martinique
    • Saint Etienne
      • Saint-Étienne, Saint Etienne, France
        • CHU Saint Etienne

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

51 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

N/A

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Multicentric prospective population in tertiary referal center for neuromuscular diseases

Description

The initial criteria before amendment

Inclusion Criteria:

  • A. Adult (>50 years old)
  • Chronic Peripheral neuropathies (progressing since 12 months),

  • Peripheral neuropathies documentated by ENMG.

    1. Chronic polyneuropathy with dysautonomia (orthostatic hypotension) without diabetes
    2. Atypical CIDP (situations C, D (even with high protid content on CSF) & E as defined by the French group for study of CIDP).
    3. Disabling neuropathy (gait or balance disorder)
    4. Neuropathies with upper limb onset who underwent previously CTS surgery without success.
    5. SLA-like syndrome : areflexia with sensory alterations on ENMG. 6: Deterioration of SNAPs' amplitudes on NCS > 30% in less than6 months by the same NCS laboratory Mandatory : A+B+C one of 1 to 6

Exclusion criteria :

  • Amyloid deposit characterized on biopsy
  • Causes of chronic polyneuropathy : Diabetes mellitus, Chronic alcoholic intoxication
  • CIDP responding to IVIg or corticosteroids (improvement by 1 point of ONLS).
  • Neuropathy associated with monoclonal gammapathy and i) anti-MAG activity or ii) POEMS syndrome or) CANOMAD syndrome.
  • Ataxic Neuropathy due to vitamine B12 deficiency
  • Ataxic Neuropathy due to IgM anti-MAG,
  • CANOMAD syndrome,
  • Ganglionopathy by Sjögren's syndrome, or paraneoplastic syndrome with Anti- Hu Antibodies, chemotherapy induced (cis-platine, oxaliplatine).
  • Positive family history of FAP or FAC
  • Proven AL amyloidosis

The new criteria after amendment New eligibility criteria from the 351st patient:

  • A. Adults > 50 years old B1. Progressive axonal polyneuropathy

Has:

  • Deterioration of EMG sensory potentials >30% in less than 6 months by the same electrophysiology team Where -. Clinical worsening over 6 months, i.e. + 1 ONLS point, or extension of sensory disorders (subjective, objective), or reduction in walking distance, or JAMAR -10% OR B2. Atypical chronic polyradiculoneuritis (CIDP)

    1. with pure sensitive
    2. pure motor
    3. . Asymmetrical sensorimotor impairment predominantly in the upper limbs
    4. Situations C, D, E -even at high protein content on CSF- and as defined by the French group for the study of CIDP C. Peripheral neuropathy evolving for ≥ 12 months and < 10 years. D. Peripheral neuropathy documented by abnormal ENMG (Electroneuromyography).

And

At least one of the following criteria:

  1. Chronic polyneuropathy with dysautonomia (orthostatic hypotension)
  2. Disabling neuropathy (walking or balance disorders, functional impairment of the hands)
  3. Unintentional weight loss of > 5 kg in the last 5 years
  4. History of operated carpal tunnel syndrome

Exclusion criteria A. Amyloid deposit characterized by biopsy B. Causes of chronic polyneuropathy: sensory neuropathy typical of diabetes mellitus, chronic alcohol intoxication (women: >14 drinks/week; men >21 drinks/week), vitamin B12 deficiency, chemotherapy (cis-Platin, oxaliplatin) C. CIDP responding to IVIG or corticosteroids (1 point improvement in ONLS) D. Peripheral neuropathy evolving for >10 years E. Dysimmune neuropathy defined by

  • with Ac anti-MAG,
  • POEMS, CANOMAD,
  • Ganglionopathy linked to Gougerot Sjögren's syndrome, to a paraneoplastic syndrome with Anti-Hu antibodies), F. Family history of FAP or FAC (familial amyloid neuropathy or cardiomyopathy) G. AL Amyloidosis

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Observational Models: Cohort
  • Time Perspectives: Prospective

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Rate of amyloidogenic TTR mutation
Time Frame: 1 day
Rate of amyloidogenic TTR mutation in progressive idiopathic polyneuropathy
1 day

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy
Time Frame: 1 day
Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : disabling neuropathy (including ataxic).
1 day
To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy :variant Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Time Frame: 1 day
Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy :variant Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
1 day
To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : upper limb onset neuropathy.
Time Frame: 1 day
Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : upper limb onset neuropathy.
1 day

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Assistance Publique - Hôpitaux de Paris

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: David ADAMS, Bicetre Hospital

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
March 17, 2017

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 30, 2021

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 10, 2021

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
December 11, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 11, 2017

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 14, 2017

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 8, 2022

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 7, 2022

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
November 1, 2022

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NI 16007

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Diagnosis

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Cookie Settings

We use cookies to ensure that we give you the best experience on our website. For more details carefully read our Privacy and Cookies Policy. ...>>>You can change your preferences or withdraw your consent at any time by deleting the cookies from your website or computer as described in the policy. Please accept it and choose your preferences by ticking the corresponding boxes in the "Manage Settings" section below. Please carefully read our Terms of Service before you proceed with using any part of this website.
«Manage Settings