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

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ClinicalTrials.gov Identifier: NCT02590276
Recruitment Status : Unknown
Verified August 2016 by Assistance Publique - Hôpitaux de Paris.
Recruitment status was:  Recruiting
First Posted : October 29, 2015
Last Update Posted : September 15, 2016
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

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:

  1. TDP-43 aggregates in neurons and
  2. 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.


Condition or disease Intervention/treatment Phase
Frontotemporal Lobar Degeneration Amyotrophic Lateral Sclerosis Behavioral: characterization Not Applicable

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

  1. 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.
  2. 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).
  3. 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.
  4. 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'.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Predict to Prevent Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis
Study Start Date : September 2015
Estimated Primary Completion Date : October 2019
Estimated Study Completion Date : October 2019


Arm Intervention/treatment
Experimental: Evaluation
Characterization
Behavioral: characterization



Primary Outcome Measures :
  1. Change in behavioral assessment (20 scales) [ Time Frame: at baseline, 16 weeks and 32weeks ]
  2. Change in MRI morphological criteria [ Time Frame: at baseline, 16 weeks and 32weeks ]
  3. Change in cerebral perfusion by SPECT / PET [ Time Frame: at baseline, 16 weeks and 32weeks ]

Secondary Outcome Measures :
  1. correlations between behavioral assessment, MRI morphological criteria, Cerebral perfusion and metabolism by SPECT / PET and transcriptome analysis [ Time Frame: 32 weeks ]


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02590276


Contacts
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Contact: LE BER Isabelle, MD, PhD 01 57 27 46 79 isabelle.leber@upmc.fr
Contact: BISSERY Anne, MD 01 42 46 24 32 anne.bissery@aphp.fr

Locations
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France
Groupe Hospitalier Pitié-Salpêtrière - Charles Foix Recruiting
Paris, France, 75013
Contact: LE BER Isabelle, MD, PhD    01 42 16 21 82 ext +(33)    isabelle.leber@upmc.fr   
Sponsors and Collaborators
Assistance Publique - Hôpitaux de Paris
Investigators
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Principal Investigator: LE BER Isabelle, MD, PhD Assistance Publique - Hôpitaux de Paris

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: Assistance Publique - Hôpitaux de Paris
ClinicalTrials.gov Identifier: NCT02590276     History of Changes
Other Study ID Numbers: P140705 -
IDRCB : 2015-A00856-43 ( Other Identifier: ANSM )
First Posted: October 29, 2015    Key Record Dates
Last Update Posted: September 15, 2016
Last Verified: August 2016
Keywords provided by Assistance Publique - Hôpitaux de Paris:
frontotemporal Dementia
Amyotrophic lateral sclerosis
Biomarkers
brain Imaging PET
Additional relevant MeSH terms:
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Motor Neuron Disease
Amyotrophic Lateral Sclerosis
Sclerosis
Frontotemporal Lobar Degeneration
Pathologic Processes
Neurodegenerative Diseases
Nervous System Diseases
Neuromuscular Diseases
Spinal Cord Diseases
Central Nervous System Diseases
TDP-43 Proteinopathies
Proteostasis Deficiencies
Metabolic Diseases
Dementia
Brain Diseases
Neurocognitive Disorders
Mental Disorders