Predict to Prevent PGRN Disease

NCT06711510 | Withdrawn

• 1 other identifier: APHP240482
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

Progranulin (GRN or PGRN) mutations are among the most common genetic causes of frontotemporal lobar degeneration (FTLD). With the advent of gene-specific therapeutic interventions, an accurate knowledge of the presymptomatic phase of the disease is of utmost importance. Increases of plasma neurofilament light chain (NfL) levels are good predictors of phenoconversion in presymptomatic carriers. However their increase rates remain partially elucidated insofar, with many confounding factors. Another point which deserves further precision is the definition of the biological onset of the disease, via the identification of markers of intraneuronal accumulation of TDP-43 protein. PREVENT-PGRN aims aims at studying the trajectory of plasma NfL changes in presymptomatic GRN mutation carriers in comparison with healthy controls, in partnership with the GENFI-QBS study. Additionally, other disease-related biomarkers, namely associated with TDP-43 pathology, will be investigated in this study, at the presymptomatic and clinical phase.

Conditions

Frontotemporal Dementia (FTD); GRN Related Frontotemporal Dementia

Keywords

Frontotemporal dementia; frontotemporal lobar degeneration; GRN; PGRN; mutation; , neurofilament light chain (NfL); biomarker; amyotrophic lateral sclerosis; primary progressive aphasia

Outcome Measures

Primary Outcomes (1)

• Compare the trajectory of plasma NfL between GRN mutation carriers, during the presymptomatic and clinical phases, and non-carrier controls, to improve identification of early disease phases and guide future therapeutic trials.

  Cross-sectional and longitudinal comparisons of NfL assays by Simoa® technique on plasma samples collected every 3 months during the 9 study visits (M0, M3, M6, M9, M12, M15, M18, M21, M24), between GRN mutation carriers and non-carrier controls.

  2 years

Secondary Outcomes (5)

• Compare the levels of other known biomarkers of interest in fluids (plasma, CSF) (such as GFAP, for example) between GRN mutation carriers, during the presymptomatic and clinical phases, and non-carrier controls.

  2 years

• Compare the trajectory of other known biomarkers of interest in fluids (plasma, CSF) mentioned above (such as GFAP, for example) between carriers of GRN gene mutations, during the presymptomatic and clinical phases, and non-carrier controls.

  2 years

• Discover new fluid biomarkers (plasma, CSF) and peripheral biomarkers (nasal mucosa, fibroblasts) targeting, in particular, the detection of the TDP-43 protein (by RT-QuIC, among others).

  2 years

• Establish correlations between biomarker trajectories and neuropsychological profiles

  2 years

• Establish correlations between biomarker trajectories and neuroimaging profiles

  2 years

Study Arms (1)

Standardized protocol for all participants

OTHER

Nine evaluations (every 3 months) over a 2-year follow-up, with the same standardized protocol for all participants, including: * At the inclusion visit (M0), after 12 months (M12) and after 24 months (M24): * clinical (neurological) evaluation * behavioral examination * cognitive testing * blood sampling (determination of carrier / non-carrier status by means of GRN testing will be done at M0 visit; results will remain strictly confidential and not disclosed to study participants and investigators) * brain MRI * olfactory swab sampling with nasal brush * skin punch biopsy (optional) * lumbar puncture for CSF sampling (optional) * For the remaining visits (M3, M6, M9, M15, M18, M21): * clinical evaluation * blood sampling

Other: Clinical, behavioral and cognitive evaluation; Other: blood sampling; Other: brain MRI; Other: olfactory swab sampling with nasal brush; Other: skin punch biopsy; Other: lumbar puncture for CSF sampling

Interventions

Clinical, behavioral and cognitive evaluation OTHER

Questionnaries and tests

Standardized protocol for all participants

blood sampling OTHER

blood sampling (56ml max)

Standardized protocol for all participants

brain MRI OTHER

brain MRI (35 to 70 minutes)

Standardized protocol for all participants

olfactory swab sampling with nasal brush OTHER

olfactory swab sampling with nasal brush

Standardized protocol for all participants

skin punch biopsy OTHER

skin punch biopsy (optional intervention)

Standardized protocol for all participants

lumbar puncture for CSF sampling OTHER

lumbar puncture for CSF sampling (optional intervention)

Standardized protocol for all participants

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• For all :
• signature of informed consent for the study
• being French speaker
• having social security coverage
• absence of any other neurological disease
• For asymptomatic at-risk individuals :
• being first-degree relative of a GRN mutation carrier OR of a patient suffering from FTD with discovery of a GRN mutation in their family
• absence of any neurological troubles related to the disease
• For patients :
• being carrier of a pathogenic GRN mutation
• diagnosis of behavioural-variant frontotemporal dementia according to Rasckvsky et al. criteria (2011) or any related clinical syndromes, such as primary progressive aphasia according to Gorno-Tempini et al. criteria (2011)

You may not qualify if:

• For all :
• any contraindication to brain MRI (pace-maker, ferromagnetic heart valve, aneurysm clips or any other ferromagnetic foreign body implanted in brain/eye or other critical locations, non-MRI compatible intrauterine devices, claustrophobia)
• chronic alcohol use / addiction
• known chronic kidney disease
• hypersensitivity to local anaesthetics
• impossibility of laying down for 1 hour without moving
• For asymptomatic at-risk individuals :
• Peaple under legal protection

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

MeSH Terms

Conditions

Frontotemporal Dementia; Frontotemporal Lobar Degeneration; Charcot-Marie-Tooth disease, Type 1F; Amyotrophic Lateral Sclerosis; Aphasia, Primary Progressive

Interventions

Blood Specimen Collection; Spinal Puncture

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; TDP-43 Proteinopathies; Neurodegenerative Diseases; Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Neurocognitive Disorders; Mental Disorders; Spinal Cord Diseases; Motor Neuron Disease; Neuromuscular Diseases; Aphasia; Speech Disorders; Language Disorders; Communication Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Biopsy; Diagnostic Techniques, Neurological; Therapeutics

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Nine evaluations (every 3 months) over a 2-year follow-up, with the same standardized protocol for all participants, including: * At the inclusion visit (M0), after 12 months (M12) and after 24 months (M24): * clinical (neurological) evaluation * behavioral examination * cognitive testing * blood sampling (determination of carrier / non-carrier status by means of GRN testing will be done at M0 visit; results will remain strictly confidential and not disclosed to study participants and investigators) * brain MRI * olfactory swab sampling with nasal brush * skin punch biopsy (optional) * lumbar puncture for CSF sampling (optional) * For the remaining visits (M3, M6, M9, M15, M18, M21): * clinical evaluation * blood sampling

Study Record Dates

• First Submitted: November 21, 2024
• First Posted: December 2, 2024
• Study Start: January 1, 2025
• Primary Completion (Estimated): March 1, 2030
• Study Completion (Estimated): March 1, 2030
• Last Updated: March 21, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share