Validation of a Prognostic Biomarker Using Brain Diffusion MRI in X-linked Adrenoleukodystrophy

NCT05911919 | Not Yet Recruiting

• 2 other identifiers: APHP220801IDRCB
• Study Type: observational
• Target: 200
• Locations: 0 countries
• Sites: N/A

Brief Summary

CALD is an inflammatory demyelinating disease that causes severe motor and cognitive deficit leading to rapid death. Hematopoietic stem cell transplantation (HSCT) can halt neuroinflammation in CALD through the replacement of microglia (i.e., brain immune system) but only if performed during its early phase. Using standard brain MRI, it is estimated that only 30% of adult CALD patients are identified. Complex and lengthy clinical evaluations together with MRI reading from experts improve CALD detection but are not available in routine clinical practice. Diffusion tensor imaging is a quantitative microstructural technique that can identify neuroinflammation at a very early stage. Still, its implementation in clinical practice has been very limited due to high inter-center measurements variability and bias due to data quality issues. The approach we will use solves these problems by introducing an automatic calibration and standardization with systematic quality control enabling the use of all MRI scanners in clinical settings. The innovative aspect of this project lies on the validation of an expert-independent prognosis biomarker able to specifically identify patients at high-risk to convert to CALD so that treatment can be initiated at the early stage of neuroinflammation. We aim to demonstrate that this tool has at least a 2-fold sensitivity compared to the current standard of care.

Conditions

X-linked Adrenoleukodystrophy

Keywords

Cerebral adrenoleukodystrophy (CALD); adrenomyeloneuropathy (AMN); ABCD1; MRI; Diffusion Tensor Imaging (DTI); Brain-Quant; Male; Adult

Outcome Measures

Primary Outcomes (2)

• Sensitivity of RD-index19 change of at least 1 point between two consecutive annual measurements to diagnose CALD before or at the same time than the reference diagnostic made by an expert committee

  The expert committee comprising 3 experts in neuroradiology blinded to the RD-index19 change results. The study aims to demonstrate that RD-index19-change of at least 1 point between two consecutive annual measurements has a sensitivity significantly greater than 60% to detect CALD conversion before or at the same time as the best experts in the field of CALD diagnosis.

  1 year, 2 years, 3 years

• Specificity of RD-index19 change of at least 1 point between two consecutive annual measurements with repect to CALD conversion before or at the same time than the reference diagnostic made by an expert committee

  The expert committee comprising 3 experts in neuroradiology blinded to the RD-index19 change results. The study aims to demonstrate that RD-index19-change of at least 1 point between two consecutive annual measurements has a specificity significantly greater than 80% with repect to CALD conversion before or at the same time as the best experts in the field of CALD diagnosis.

  1 year, 2 years, 3 years

Secondary Outcomes (16)

• Sensitivity values of plasma NfL with regard to CALD diagnosis

  1 year, 2 years, 3 years

• Specificity values of plasma NfL with regard to CALD diagnosis

  1 year, 2 years, 3 years

• Sensitivity values of FA-index19-change with regard to CALD diagnosis

  1 year, 2 years, 3 years

• Specificity values of FA-index19-change with regard to CALD diagnosis

  1 year, 2 years, 3 years

• Sensitivity values of MD-index19-change with regard to CALD diagnosis

  1 year, 2 years, 3 years

Study Arms (2)

Patients

Patients with ABCD1 pathogenic variant

Device: brainQuant module of brainTale-care platform

Healthy volunteers

Healthy volunteers inclusion in order to calibrate the MRI machine used and its settings.

Interventions

brainQuant module of brainTale-care platform DEVICE

brainQuant is a software module of brainTale-care medical device (a medical device software as a service (web platform) ) for the automatic processing of brain diffusion Magnetic resonance images and the provision of the diffusion regional standardised parameters.

Patients

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Patients: Adult males carrying an ABCD1 pathogenic variant. Since ABCD1 is localised in X chromosome, CALD affects quasi-exclusively the male population and less than 1% of ABCD1 female carriers are at risk to develop the cerebral inflammatory form of the disease
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Adult males carrying an ABCD1 pathogenic variant

You may qualify if:

• \> 18 years old
• Male gender
• Genetically diagnosed with ALD by carrying an ABCD1 pathogenic variant
• Signed written informed consent
• Affiliation to a social security regime (patient with AME cannot be included)

You may not qualify if:

• Patient with non-arrested CALD
• Other neurological conditions such as brain tumour, stroke or a traumatic head injury
• Contraindication to MRI (claustrophobia, implanted metal components in the head, panic disorder, epilepsy)
• People under legal protection measure (tutorship, curatorship or safeguard measures)
• Patient included in another interventional clinical trial
• Healthy volunteers
• Male or female subject from 18 to 65 years old
• In general good health condition
• Signed written informed consent
• Affiliation to a social security regime (healthy volunteers with AME cannot be enrolled)
• People under legal protection measure (tutorship, curatorship or safeguard measures)
• Contraindication to MRI (claustrophobia, implanted metal components in the head, panic disorder, epilepsy)
• History of previous brain disease (including but not limited to cranial trauma in the last 12 months, glioma, stroke, neurodegenerative diseases)
• Arterial hypertension as defined in WHO criteria
• Volunteer included in another interventional clinical trial

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Braintale: collaborator

Biospecimen

Retention: SAMPLES WITHOUT DNA

Only for Patient group : Plasma and PBMC (Peripheral Blood Mononuclear Cells) collections

MeSH Terms

Conditions

Adrenoleukodystrophy

Condition Hierarchy (Ancestors)

Brain Diseases, Metabolic, Inborn; Brain Diseases, Metabolic; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Hereditary Central Nervous System Demyelinating Diseases; Leukoencephalopathies; Demyelinating Diseases; X-Linked Intellectual Disability; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Genetic Diseases, X-Linked; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Heredodegenerative Disorders, Nervous System; Metabolism, Inborn Errors; Peroxisomal Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Adrenal Insufficiency; Adrenal Gland Diseases; Endocrine System Diseases

Study Officials

• Fanny MOCHEL, MD, PhD

  APHP - Pitié-Salpêtrière Hospital

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Fanny MOCHEL, MD, PhD

CONTACT

+33157274482; fanny.mochel@upmc.fr

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 12, 2023
• First Posted: June 22, 2023
• Study Start: September 1, 2023
• Primary Completion (Estimated): September 1, 2028
• Study Completion (Estimated): September 1, 2028
• Last Updated: July 3, 2023

Record last verified: 2023-06

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Beginning 3 months and ending 3 years following article publication. Requests out of these time frame can also be submitted to the sponsor.
• Access Criteria: Researchers who provide a methodologically sound proposal.