search
Back to results

Expanding the Biomarkers in Familial Amyloid Neuropathy: MRI and Motor Unit Estimation by Electrophysiological Study

Primary Purpose

Amyloid Neuropathies, Transthyretin Amyloidosis

Status
Completed
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Electrophysiological biomarkers
MRI biomarkers
Sponsored by
Assistance Publique Hopitaux De Marseille
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional diagnostic trial for Amyloid Neuropathies

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

For a subject to be eligible, all of the inclusion criteria and none of the exclusion criteria must be met.

3.1.1. TTR mutation gene carriers 3.1.1.a. Inclusion criteria

Subject must meet the following criteria to be included:

  • 18 years and older
  • Men or women
  • Carrying TTR mutation
  • Having social insurance
  • Given written informed consent after being informed of the purpose and potential risks

3.1.1.b. Exclusion criteria

Subjects with the following criteria will be excluded:

  • Subject with a contraindication for MRI explorations
  • Subject unable to understand the purpose and conditions of carrying out the study, unable to give consent

3.1.2. Healthy controls 3.1.2.a. Inclusion criteria

Subject must meet the following criteria to be included:

  • 18 years and older
  • Men or women
  • Having social insurance
  • Given written informed consent after being informed of the purpose and potential risks

3.1.2.b. Exclusion criteria

Subjects with the following criteria will be excluded:

  • Subject with a contraindication for MRI explorations
  • Subject unable to understand the purpose and conditions of carrying out the study, unable to give consent

Sites / Locations

  • Assistance Publique Des Hopitaux de Marseille

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Sham Comparator

Active Comparator

Experimental

Arm Label

healthy

Asymptomatic carriers

Symptomatic carriers

Arm Description

will be defined as persons without pathological mutation of the TTR gene Electrophysiological biomarkers and MRI biomarkers will be performed

will be defined as persons with a known pathological mutation of the TTR gene but with no clinical complain, normal clinical examination, and normal renal and cardiac investigations. Electrophysiological biomarkers and MRI biomarkers will be performed

will be defined as persons with a known pathological mutation of the TTR gene with clinical complain, abnormal clinical examination, and abnormal renal and cardiac investigations. Electrophysiological biomarkers and MRI biomarkers will be performed

Outcomes

Primary Outcome Measures

MRI neurography
surface and diameter of the sciatic nerve will be measured on the T1-weighted sequence. Quantitative analyses will be performed using T2 and MTR sequences on the sciatic nerve at the middle of the thigh.
MUNIX
Supramaximal distal stimulations of the corresponding nerves will be performed to achieve maximal CMAP amplitude with minimum rise time and sharp negative take-off.

Secondary Outcome Measures

Full Information

First Posted
July 4, 2018
Last Updated
October 2, 2022
Sponsor
Assistance Publique Hopitaux De Marseille
search

1. Study Identification

Unique Protocol Identification Number
NCT03588468
Brief Title
Expanding the Biomarkers in Familial Amyloid Neuropathy: MRI and Motor Unit Estimation by Electrophysiological Study
Official Title
Expanding the Biomarkers in Familial Amyloid Neuropathy: Magnetic Resonance Imaging (MRI) and Motor Unit Estimation by Electrophysiological Study
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Completed
Study Start Date
September 20, 2018 (Actual)
Primary Completion Date
December 18, 2019 (Actual)
Study Completion Date
December 18, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique Hopitaux De Marseille

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Familial amyloid neuropathies (FAP) are hereditary disease due to a mutation of the tranthyretin gene (TTR). These neuropathies are severe and life frightening. Asymptomatic carrier of TTR mutation are now detected in large TTR-FAP family. However, it is very hard to detect the moment where a TTR mutation carrier become symptomatic: too early diagnosis exposes the patients to side effect of the treatment and too late diagnosis exposes the patient to disease progression and clinical sequels. Neurological monitoring comprises clinical examination, electrophysiology and imaging. Sensitivity and specificity of these tools are not sufficient and we have to develop new biomarkers sensitive enough to detect modifications under treatment and the moment where a TTR mutation carrier become symptomatic Magnetic resonance imaging (MRI) can well evaluate neuromuscular diseases. Electrophysiological examination is also a good tool to evaluate NAF. MUNIX is a technique that permits to estimate the number of motor unit in one muscl. MUNIX is related to the disability in chronic inflammatory neuropathies and could be more sensitive than clinical scales and other electrophysiological data to detect modification of the disease in TTR-FAP. The objective of this exploratory study is to test the applicability of MUNIX and MRI as early measures for detecting the transition from asymptomatic to symptomatic TTR-FAP. In symptomatic TTR-FAP we will determine if MUNIX and MRI data are related to clinical deficiency and disability of the patients. This is a transversal exploratory study. If we manage to demonstrate that MRI and MUNIX can segregate symptomatic versus asymptomatic TTR mutation gene carriers, we will propose a longitudinal study with a follow up of more asymptomatic gene carriers.
Detailed Description
Familial amyloid neuropathies (FAP) are hereditary disease due to a mutation of the tranthyretin gene (TTR). These neuropathies are severe and life frightening. Treatment is based on tafamidis and liver transplantation. Clinical trials of RNAI therapy are on-going. Treatment must be performed early to avoid clinical consequences. Asymptomatic carrier of TTR mutation are now detected in large TTR-FAP family. Time of the beginning of the disease is quite variable among the patients and very difficult to predict. Penetrance is low and incomplete. It is estimated to be respectively 1.7% and 69% at the age of 30 and 90 years in the Swedish population. It is very hard to detect the moment where a TTR mutation carrier become symptomatic: too early diagnosis exposes the patients to side effect of the treatment and too late diagnosis exposes the patient to disease progression and clinical sequels. Neurological monitoring comprises clinical examination, electrophysiology and imaging. Sensitivity and specificity of these tools are not sufficient and we have to develop new biomarkers sensitive enough to detect modifications under treatment and the moment where a TTR mutation carrier become symptomatic Magnetic resonance imaging (MRI) can well evaluate neuromuscular diseases. Nerve and muscle magnetization transfer are related to the disability in peripheral neuropathies. Specific MRI protocols permit to distinguish healthy control, asymptomatic carrier and symptomatic carrier of TTR mutation. In Kollmer et al study[9], high-resolution magnetic resonance neurography was applied at the thigh of 13 patients with symptomatic polyneuropathy and seven asymptomatic gene carriers. Quantification of mean proton spin density and T2 relaxation time was significantly different in symptomatic and asymptomatic TTR mutation gene carriers. Electrophysiological examination is also a good tool to evaluate NAF. MUNIX is a technique that permits to estimate the number of motor unit in one muscle. MUNIX has been applied in large population of athletes and in chronic neurologic disorders as Amyotrophic Lateral Sclerosis (ALS) and inflammatory neuropathies. MUNIX is related to the disability in chronic inflammatory neuropathies, and It is more sensitive than clinical scales to detect the worsening of the disease in ALS. In TTR-FAP, the loss of motor unit is compensated by collateral sprouting of the terminal axons. Muscle weakness and muscle atrophy are delayed in the evolution of the disease and the involvement of the motor unit is not clinically detected in the early stage of the disease. We hypothesize that the variation of the MUNIX could be more sensitive than clinical scales and other electrophysiological data to detect modification of the disease in TTR-FAP. The objective of this exploratory study is to test the applicability of MUNIX and MRI as early measures for detecting the transition from asymptomatic to symptomatic TTR-FAP. In symptomatic TTR-FAP we will determine if MUNIX and MRI data are related to clinical deficiency and disability of the patients. This is a transversal exploratory study. If we manage to demonstrate that MRI and MUNIX can segregate symptomatic versus asymptomatic TTR mutation gene carriers, we will propose a longitudinal study with a follow up of more asymptomatic gene carriers. Will be included 10 healthy controls, and 15 TTR mutation gene carriers comprising 5 asymptomatic carriers and 10 symptomatic carriers. The sample size may look small, but it is similar to other published studies. Kollmer et al analysed magnetic resonance neurography in 13 symptomatic TTR-FAP and 7 asymptomatic gene carriers. In our study about MUNIX in inflammatory neuropathies, the analyse of 14 patients had enough statistical power to demonstrate that the MUNIX was related to the disability. Furthermore, TTR-FAP is a rare disease with a prevalence of 1 in 100 000, so we had to adapt the sample size is to an exploratory monocentric study. Furthermore, symptomatic TTR-FAP patients have frequently pace maker which prevent MRI assessment and will exclude patients from this study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Amyloid Neuropathies, Transthyretin Amyloidosis

7. Study Design

Primary Purpose
Diagnostic
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
60 (Actual)

8. Arms, Groups, and Interventions

Arm Title
healthy
Arm Type
Sham Comparator
Arm Description
will be defined as persons without pathological mutation of the TTR gene Electrophysiological biomarkers and MRI biomarkers will be performed
Arm Title
Asymptomatic carriers
Arm Type
Active Comparator
Arm Description
will be defined as persons with a known pathological mutation of the TTR gene but with no clinical complain, normal clinical examination, and normal renal and cardiac investigations. Electrophysiological biomarkers and MRI biomarkers will be performed
Arm Title
Symptomatic carriers
Arm Type
Experimental
Arm Description
will be defined as persons with a known pathological mutation of the TTR gene with clinical complain, abnormal clinical examination, and abnormal renal and cardiac investigations. Electrophysiological biomarkers and MRI biomarkers will be performed
Intervention Type
Other
Intervention Name(s)
Electrophysiological biomarkers
Intervention Description
Motor and sensory nerve conduction study will be performed on median, ulnar, tibialis, peroneal and sural nerves.
Intervention Type
Other
Intervention Name(s)
MRI biomarkers
Intervention Description
T1, T2, STIR and magnetisation transfer ratio (MTR) will be performed unilaterally on the thigh and the leg.
Primary Outcome Measure Information:
Title
MRI neurography
Description
surface and diameter of the sciatic nerve will be measured on the T1-weighted sequence. Quantitative analyses will be performed using T2 and MTR sequences on the sciatic nerve at the middle of the thigh.
Time Frame
1 hour
Title
MUNIX
Description
Supramaximal distal stimulations of the corresponding nerves will be performed to achieve maximal CMAP amplitude with minimum rise time and sharp negative take-off.
Time Frame
30 minutes

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
For a subject to be eligible, all of the inclusion criteria and none of the exclusion criteria must be met. 3.1.1. TTR mutation gene carriers 3.1.1.a. Inclusion criteria Subject must meet the following criteria to be included: 18 years and older Men or women Carrying TTR mutation Having social insurance Given written informed consent after being informed of the purpose and potential risks 3.1.1.b. Exclusion criteria Subjects with the following criteria will be excluded: Subject with a contraindication for MRI explorations Subject unable to understand the purpose and conditions of carrying out the study, unable to give consent 3.1.2. Healthy controls 3.1.2.a. Inclusion criteria Subject must meet the following criteria to be included: 18 years and older Men or women Having social insurance Given written informed consent after being informed of the purpose and potential risks 3.1.2.b. Exclusion criteria Subjects with the following criteria will be excluded: Subject with a contraindication for MRI explorations Subject unable to understand the purpose and conditions of carrying out the study, unable to give consent
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
EMILIE GARRIDO PRADALIE
Organizational Affiliation
APHM
Official's Role
Study Director
Facility Information:
Facility Name
Assistance Publique Des Hopitaux de Marseille
City
Marseille
State/Province
Paca
ZIP/Postal Code
13354
Country
France

12. IPD Sharing Statement

Learn more about this trial

Expanding the Biomarkers in Familial Amyloid Neuropathy: MRI and Motor Unit Estimation by Electrophysiological Study

We'll reach out to this number within 24 hrs