PolyneuropathyADDITIONNCT03373370
Early Diagnosis of TTR Amyloidosis by Use of Molecular Biology
An observational study of Polyneuropathy and Diagnosis, run by Assistance Publique - Hôpitaux de Paris at 10 sites in France.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 51 years and older
- Conditions the study is for
- Polyneuropathy, Diagnosis, Idiopathic Progressive Neuropathy
- How many people
- 560 participants
- Where
- 10 sitesFrance
- Study dates
- 17 Mar 2017to 10 Dec 2021
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 51 years and older
- All sexes
- Adult, Older adult
Study population: Multicentric prospective population in tertiary referal center for neuromuscular diseases
Who may be able to join
- A. Adult (>50 years old)
- Chronic Peripheral neuropathies (progressing since 12 months),
- Peripheral neuropathies documentated by ENMG.
- Chronic polyneuropathy with dysautonomia (orthostatic hypotension) without diabetes
- Atypical CIDP (situations C, D (even with high protid content on CSF) \& E as defined by the French group for study of CIDP).
- Disabling neuropathy (gait or balance disorder)
- Neuropathies with upper limb onset who underwent previously CTS surgery without success.
- 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
Who cannot join
- 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,
Show all 28Show fewer
- 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)
- with pure sensitive
- pure motor
- . Asymmetrical sensorimotor impairment predominantly in the upper limbs
- 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:
- Chronic polyneuropathy with dysautonomia (orthostatic hypotension)
- Disabling neuropathy (walking or balance disorders, functional impairment of the hands)
- Unintentional weight loss of > 5 kg in the last 5 years
- 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
Trial locations and contacts
10 sites in 1 country.
10 sites in 1 country
France10 sites
CHU Grenoble
Grenoble, 38043
Chu Bicetre
Le Kremlin-Bicêtre, Kremlin Bicetre, 94270
CHRU Lille
Lille, 59037
CHU Dupuytren
Limoges, 87042
CHU La Timone
Marseille, 13000
CHU Martinique
Martigues, Martinique, 97200
Hopital guy-de-Chauliac
Montpellier, 34295
Hôpital de La Salpetrière
Paris, 75013
CHU Saint Etienne
Saint-Etienne, Saint Etienne
Hopital de Hautepierre
Strasbourg, 67098
About this study
Official title: 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.
Read more
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.
Read the 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.
- Conditions
- Polyneuropathy, Diagnosis, Idiopathic Progressive Neuropathy
- Medical subject headings
- Polyneuropathies, Disease
What is being measured
The primary outcome is the main question the study is designed to answer.
Rate of amyloidogenic TTR mutation
Rate of amyloidogenic TTR mutation in progressive idiopathic polyneuropathy
Measured: 1 day
Secondary outcomes (3)
To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy
Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : disabling neuropathy (including ataxic).
Measured: 1 day
To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy :variant Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy :variant Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)
Measured: 1 day
To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : upper limb onset neuropathy.
Rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : upper limb onset neuropathy.
Measured: 1 day
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Dec 2017
- Study start17 Mar 2017
- Primary completion30 Sep 2021
- Study completion10 Dec 2021
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for PolyneuropathyStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 560 participants (actual)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- David ADAMS, Principal investigator, Bicetre Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03373370
- Sponsor's protocol ID
- NI 16007
- Acronym
- ADDITION
- Status last verified
- Nov 2022
- First submitted
- 11 Dec 2017
- Last updated
- 8 Dec 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 8 Dec 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Project to Accelerate the Diagnosis of TTR Amyloidosis by Use of Molecular Biology in First Intention
- ClinicalTrials.gov ID
- NCT03373370
- Acronym / sponsor ID
- ADDITION / NI 16007
- Conditions
- Polyneuropathy, Diagnosis, Idiopathic Progressive Neuropathy
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 560 participants (actual)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 17 Mar 2017 (actual)
- Primary completion
- 30 Sep 2021 (actual)
- Study completion
- 10 Dec 2021 (actual)
- First posted
- 14 Dec 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 design
- Observational model
- Cohort
- Time perspective
- Prospective
Who may qualify
- Ages
- 51 years and older
- Sex
- All
- Age groups
- Adult, Older adult
- Study population
- Multicentric prospective population in tertiary referal center for neuromuscular diseases
Key inclusion criteria (8 listed)
- A. Adult (>50 years old)
- Chronic Peripheral neuropathies (progressing since 12 months),
- Peripheral neuropathies documentated by ENMG.
Key exclusion criteria (28 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Rate of amyloidogenic TTR mutation
Time frame: 1 day
Rate of amyloidogenic TTR mutation in progressive idiopathic polyneuropathy
3 secondary outcomes
To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy
Time frame: 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
To identify the rate of amyloidogenic TTR mutation in different subgroups of patients with neuropathy : upper limb onset neuropathy.
Time frame: 1 day
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Dec 2022.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David ADAMS principal investigator
Bicetre Hospital
10 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Polyneuropathy and Diagnosis, run by Assistance Publique - Hôpitaux de Paris at 10 sites in France.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 Dec 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 10 sites in France. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Rate of amyloidogenic TTR mutation (time frame: 1 day). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Dec 2022.