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Predict to Prevent Frontotemporal Lobar Degeneration (FDT) and Amyotrophic Lateral Sclerosis (ALS) (PREV-DEMALS)

Primary Purpose

Frontotemporal Lobar Degeneration, Amyotrophic Lateral Sclerosis

Status

Completed

Phase

Not Applicable

Locations

France

Study Type

Interventional

Intervention

characterization

About this trial

This is an interventional prevention trial for Frontotemporal Lobar Degeneration focused on measuring frontotemporal Dementia, Amyotrophic lateral sclerosis, Biomarkers, brain Imaging PET

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Age ≥ 18
Signed informed consent for genetic and clinical study
To be carrier of a C9ORF72 mutation - Diagnosis criteria of FTD or ALS
To be French-speaking
To be affiliated to the social security scheme
Absence of another intercurrent neurological pathology (vascular cerebral accident, tumor, etc.....)

Inclusion criteria for asymptomatic relatives

Age ≥ 18
To be first degree relative of a person carrying a C9ORF72 mutation OR first degree relative of FTD or ALS deceased patient whose C9ORF72 mutation as been identified in the family
Signed informed consent for genetic and clinical study
To be French-speaking
To be affiliated to the social security scheme
Absence of proven neurologic disorders or an intercurrent neurological pathology (vascular cerebral accident, tumor, etc.....)

Exclusion Criteria:

Contra-indication to perform a brain MRI (wearing of pacemaker, cardiac valve or incompatible vascular MRI surgical equipment , neurosurgery or surgery vascular equipment, surgical equipment likely to concentrate the radio frequency field, intra ocular or intra cerebral metal foreign body, claustrophobia, wearing a non-compliant radio intrauterine device ),
Inability to lie one hour without moving
PET-FDG contra-indication
Breastfeeding and pregnant women
Human chorionic gonadotrophin (Bétâ-HCG) positive determination or Positive urine pregnancy test for women of childbearing age

Exclusion criteria for related asymptomatic :

Clinical proven signs of FTD, language disorder, praxis disorder, mnemic, of parkinson's syndrome or amyotrophic lateral sclerosis.
Counter-indication to perform a brain MRI (wearing of pacemaker, cardiac valve or incompatible vascular MRI surgical equipment , neurosurgery or surgery vascular equipment, surgical equipment likely to concentrate the radio frequency field, intra ocular or intra cerebral metal foreign body, claustrophobia, wearing a non-compliant radio intrauterine device )
Severe chronic alcoholism
PET-FDG contre-indication
Inability to lie one hour without moving
Bétâ-HCG positive determination or Positive urine pregnancy test for women of childbearing age

Sites / Locations

Groupe Hospitalier Pitié-Salpêtrière - Charles Foix

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Evaluation

Arm Description

Characterization

Outcomes

Primary Outcome Measures

Change in behavioral assessment (20 scales)

Change in MRI morphological criteria

Change in cerebral perfusion by SPECT / PET

Secondary Outcome Measures

correlations between behavioral assessment, MRI morphological criteria, Cerebral perfusion and metabolism by SPECT / PET and transcriptome analysis

Full Information

NCT ID

NCT02590276

First Posted

October 5, 2015

Last Updated

January 15, 2021

Sponsor

Assistance Publique - Hôpitaux de Paris

1. Study Identification

Unique Protocol Identification Number

NCT02590276

Brief Title

Predict to Prevent Frontotemporal Lobar Degeneration (FDT) and Amyotrophic Lateral Sclerosis (ALS)

Acronym

PREV-DEMALS

Official Title

Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Study Type

Interventional

2. Study Status

Record Verification Date

August 2016

Overall Recruitment Status

Completed

Study Start Date

October 8, 2015 (Actual)

Primary Completion Date

October 27, 2020 (Actual)

Study Completion Date

October 27, 2020 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Assistance Publique - Hôpitaux de Paris

4. Oversight

Data Monitoring Committee

5. Study Description

Brief Summary

The project focuses on C9orf72, the most frequent genetic form of frontotemporal dementias (FTD, or frontotemporal lobar degeneration, FTLD) and amyotrophic lateral sclerosis (ALS). FTD is the second commonest cause of degenerative dementia in presenium after Alzheimer's disease. Behavioural and cognitive impairments progressively lead to dementia. ALS produces progressive muscle weakness leading to the death in 2 to 4 years. Since 2006, major discoveries have linked FTLD and ALS: TDP-43 aggregates in neurons and C9orf72 mutations is a major genetic cause in both disorders. Two major pathological subtypes are now defined in FTD, FTD-TDP and FTD-TAU. C9orf72 mutations (associated to FTD-TDP) are the most frequent genetic causes of FTD (15%), FTD-ALS (65%) and ALS (40%). FTD is difficult at an early stage; and no clinical, biological or imaging features can predict the underlying pathology in living patients. Therapeutic perspectives emerged against tau aggregation, progranulin deficit and C9orf72 expansion (antisense). Presymptomatic carriers of genetic FTD would benefit, before onset of symptoms, from these therapeutic that would delay or prevent the disease. At this step, it becomes crucial to develop markers to know how many years before symptoms, does the pathological progress begin, to treat the patients at the most early stage of the disease. Markers are also needed to predict the pathology (FTD-TDP/FTD-tau) in patients that will be eligible for trials targeting specific pathological lesion.

Detailed Description

This study will investigate whether cognitive deficits, structural and functional changes can be detected before symptom onset in presymptomatic mutation carrier. The main objectives of the project are to identify novel cognitive, brain imaging markers and peripheral biomarkers for early diagnosis of FTLD, and to follow disease progression. Methodology Recruitment and evaluation of participants, neurological, behaviour and cognition evaluations. One hundred participants including 20 C9orf72 patients and 80 'a-risk' individuals will be recruited and evaluated by clinical partners of the project (Paris, Lille, Limoges, Rouen).. 'At-risk individuals' are the first degree relatives of C9ORF72 patients, who have a high a risk (50%) to carry the mutation. Identifying brain structural markers. Brain structural changes will be evaluated by voxel-based morphometry (SPM12 software) to assess global brain atrophy and evaluation of atypical shape patterns such as cortical thickness (Freesurfer software) and study of the cortical sulci (BrainVISA/Morphologist software). Identifying brain metabolic markers by Fluoro Deoxy DGlucose-Positron Emission Tomography (FDG-PET). We will apply voxel-based methods using Statistical Parametric Mapping software (SPM8) to compare different groups or analyze correlations between brain metabolism and cognitive deficits. Identifying peripheral biomarkers of disease onset and disease progression. We propose to use RNA sequencing to study gene expression and RNA splicing alterations in lymphocytes of C9ORF72 patients and 'at risk individuals'.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Frontotemporal Lobar Degeneration, Amyotrophic Lateral Sclerosis

Keywords

frontotemporal Dementia, Amyotrophic lateral sclerosis, Biomarkers, brain Imaging PET

7. Study Design

Primary Purpose

Prevention

Study Phase

Not Applicable

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Evaluation

Arm Type

Experimental

Arm Description

Characterization

Intervention Type

Behavioral

Intervention Name(s)

characterization

Primary Outcome Measure Information:

Title

Change in behavioral assessment (20 scales)

Time Frame

at baseline, 16 weeks and 32weeks

Title

Change in MRI morphological criteria

Time Frame

at baseline, 16 weeks and 32weeks

Title

Change in cerebral perfusion by SPECT / PET

Time Frame

at baseline, 16 weeks and 32weeks

Secondary Outcome Measure Information:

Title

correlations between behavioral assessment, MRI morphological criteria, Cerebral perfusion and metabolism by SPECT / PET and transcriptome analysis

Time Frame

32 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Age ≥ 18 Signed informed consent for genetic and clinical study To be carrier of a C9ORF72 mutation - Diagnosis criteria of FTD or ALS To be French-speaking To be affiliated to the social security scheme Absence of another intercurrent neurological pathology (vascular cerebral accident, tumor, etc.....) Inclusion criteria for asymptomatic relatives Age ≥ 18 To be first degree relative of a person carrying a C9ORF72 mutation OR first degree relative of FTD or ALS deceased patient whose C9ORF72 mutation as been identified in the family Signed informed consent for genetic and clinical study To be French-speaking To be affiliated to the social security scheme Absence of proven neurologic disorders or an intercurrent neurological pathology (vascular cerebral accident, tumor, etc.....) Exclusion Criteria: Contra-indication to perform a brain MRI (wearing of pacemaker, cardiac valve or incompatible vascular MRI surgical equipment , neurosurgery or surgery vascular equipment, surgical equipment likely to concentrate the radio frequency field, intra ocular or intra cerebral metal foreign body, claustrophobia, wearing a non-compliant radio intrauterine device ), Inability to lie one hour without moving PET-FDG contra-indication Breastfeeding and pregnant women Human chorionic gonadotrophin (Bétâ-HCG) positive determination or Positive urine pregnancy test for women of childbearing age Exclusion criteria for related asymptomatic : Clinical proven signs of FTD, language disorder, praxis disorder, mnemic, of parkinson's syndrome or amyotrophic lateral sclerosis. Counter-indication to perform a brain MRI (wearing of pacemaker, cardiac valve or incompatible vascular MRI surgical equipment , neurosurgery or surgery vascular equipment, surgical equipment likely to concentrate the radio frequency field, intra ocular or intra cerebral metal foreign body, claustrophobia, wearing a non-compliant radio intrauterine device ) Severe chronic alcoholism PET-FDG contre-indication Inability to lie one hour without moving Bétâ-HCG positive determination or Positive urine pregnancy test for women of childbearing age

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

LE BER Isabelle, MD, PhD

Organizational Affiliation

Assistance Publique - Hôpitaux de Paris

Official's Role

Principal Investigator

Facility Information:

Facility Name

Groupe Hospitalier Pitié-Salpêtrière - Charles Foix

City

Paris

ZIP/Postal Code

75013

Country

France

12. IPD Sharing Statement

Citations:

PubMed Identifier

34349004

Citation

Saracino D, Dorgham K, Camuzat A, Rinaldi D, Rametti-Lacroux A, Houot M, Clot F, Martin-Hardy P, Jornea L, Azuar C, Migliaccio R, Pasquier F, Couratier P, Auriacombe S, Sauvee M, Boutoleau-Bretonniere C, Pariente J, Didic M, Hannequin D, Wallon D; French Research Network on FTD/FTD-ALS; PREV-DEMALS and Predict-PGRN study groups; Colliot O, Dubois B, Brice A, Levy R, Forlani S, Le Ber I. Plasma NfL levels and longitudinal change rates in C9orf72 and GRN-associated diseases: from tailored references to clinical applications. J Neurol Neurosurg Psychiatry. 2021 Dec;92(12):1278-1288. doi: 10.1136/jnnp-2021-326914. Epub 2021 Aug 4.

Results Reference

derived

PubMed Identifier

33239440

Citation

Kmetzsch V, Anquetil V, Saracino D, Rinaldi D, Camuzat A, Gareau T, Jornea L, Forlani S, Couratier P, Wallon D, Pasquier F, Robil N, de la Grange P, Moszer I, Le Ber I, Colliot O, Becker E; PREV-DEMALS study group. Plasma microRNA signature in presymptomatic and symptomatic subjects with C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2021 May;92(5):485-493. doi: 10.1136/jnnp-2020-324647. Epub 2020 Nov 25.

Results Reference

derived

PubMed Identifier

31177556

Citation

Querin G, Bede P, El Mendili MM, Li M, Pelegrini-Issac M, Rinaldi D, Catala M, Saracino D, Salachas F, Camuzat A, Marchand-Pauvert V, Cohen-Adad J, Colliot O, Le Ber I, Pradat PF; Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis Study Group. Presymptomatic spinal cord pathology in c9orf72 mutation carriers: A longitudinal neuroimaging study. Ann Neurol. 2019 Aug;86(2):158-167. doi: 10.1002/ana.25520. Epub 2019 Jun 27.

Results Reference

derived

PubMed Identifier

30355607

Citation

Wen J, Zhang H, Alexander DC, Durrleman S, Routier A, Rinaldi D, Houot M, Couratier P, Hannequin D, Pasquier F, Zhang J, Colliot O, Le Ber I, Bertrand A; Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis (PREV-DEMALS) Study Group. Neurite density is reduced in the presymptomatic phase of C9orf72 disease. J Neurol Neurosurg Psychiatry. 2019 Apr;90(4):387-394. doi: 10.1136/jnnp-2018-318994. Epub 2018 Oct 24.

Results Reference

derived

PubMed Identifier

29197216

Citation

Bertrand A, Wen J, Rinaldi D, Houot M, Sayah S, Camuzat A, Fournier C, Fontanella S, Routier A, Couratier P, Pasquier F, Habert MO, Hannequin D, Martinaud O, Caroppo P, Levy R, Dubois B, Brice A, Durrleman S, Colliot O, Le Ber I; Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis (PREV-DEMALS) Study Group. Early Cognitive, Structural, and Microstructural Changes in Presymptomatic C9orf72 Carriers Younger Than 40 Years. JAMA Neurol. 2018 Feb 1;75(2):236-245. doi: 10.1001/jamaneurol.2017.4266. Erratum In: JAMA Neurol. 2019 May 13;:

Results Reference

derived

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Predict to Prevent Frontotemporal Lobar Degeneration (FDT) and Amyotrophic Lateral Sclerosis (ALS)

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