Innovative Imaging and Cognitive BIOmarkers to Predict Huntington's Disease Progression (I2BIO-HD)

Intro Huntington's disease (HD) patients suffer from motor, cognitive and behavioral impairments, with heterogeneous phenotypes and variable time course. This leads to a high variance of HD markers, none of which is currently sensitive enough to 1) measure disease progression from small cohort data, 2) predict disease entry in carriers of the HD mutation (during the prodromal phase or in patients considered asymptomatic: pre-HD patients), and 3) measure a significant evolution of the state of pre-HD patients over a time window compatible with the realization of clinical trials (about 2/3 years). Moreover, the markers of HD do not allow a fine stratification of the patients.

Hypothesis/Objective Our objectives are 1) to evaluate the sensitivity of new markers and assessment tools for symptomatic (HD) and presymptomatic (pre-HD) patients, 2) to define a model of disease progression, and 3) to establish an enrichment strategy to improve patient selection for future therapeutic trials.

Method We will evaluate newly developed cognitive tests, multimodal imaging techniques, biological markers and use innovative statistical approaches.

We will follow 60 patients with the mutation responsible for MH (40 presymptomatic pre-MH patients, 20 symptomatic MH patients) and 20 healthy volunteers (controls) over a 24-month period.

Study Overview

• Status: Not yet recruiting
• Conditions: Huntington Disease
• Intervention / Treatment: Radiation: radiotracer injection

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Anne-Catherine BACHOUD-LEVI, PhD; Phone Number: (+33)1 49 81 23 10; Email: anne-catherine.bachoud-levi@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• For all participants:
• Age ≥18 years and ≤65 years
• Information and collection of written consent
• Affiliation with a social security plan, beneficiary or beneficiary's right
• Healthy controls
• UHDRS functional score TFC = 13
• Motor UHDRS score TMS < 6 With no known genetic disease and no direct relationship to an HD patient or family ancestors carrying the HD mutation (or knowing their genetic status with CAG < 36).
• Manifest carriers
• Number of GACs ≥ 40
• CAP score ≥ 250
• 10 ≤ TFC ≤ 13
• TMS >5 if TFC=13
• Diagnostic confidence level =4
• Age of onset of disease > 20 years
• Patients physically able to sign consent
• Premanifest carriers
• Number of GACs ≥ 40
• CAP score ≥250
• CFT = 13
• TMS < 6
• Patients physically able to sign consent

Exclusion Criteria:

• Participant under guardianship or curatorship
• Neurological or psychiatric disorder unrelated to HD
• Intercurrent illness that may impact participant's performance
• Chronic progressive neurological disease
• Claustrophobia
• Brain injury unrelated to HD
• Pacemaker, intracorporeal metal, intracerebral clip, any metallic foreign body: implantable cardiac electronic device such as pacemakers, implantable cardioverter defibrillators etc., metallic intraocular foreign bodies, implantable neurostimulation systems, cochlear implants/ear implants, drug infusion pumps (insulin administration, analgesic drugs), or chemotherapy pumps): if possible, the patient should remove the device.
• Catheters with metal components (Swan-Ganz catheter), metal fragments such as bullets, shotgun pellets and metal shrapnel, cerebral artery aneurysm clips, magnetic dental implants, tissue expander, artificial limb, hearing aid, piercing such as pacemaker,
• Known hypersensitivity to the radiopharmaceutical preparation (excipients in the radiopharmaceutical preparation)
• Pregnant or breastfeeding woman
• Person under state medical aid
• Person deprived of liberty
• Person participating or having participated in an interventional study for less than 3 months or without time limit in a trial of neural transplants or gene therapy.
• Person participating or having participated in a research protocol with a radiopharmaceutical injection for less than 12 months.
• Neurological or psychiatric disorder unrelated to HD
• Intercurrent disease that may impact participant's performance
• Chronic progressive neurological disease
• Claustrophobia
• Brain injury unrelated to HD
• Pacemaker, intracorporeal metal, intracerebral clip
• Pregnant, breastfeeding or wanting to procreate during participation in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Symptomatic (MH) and pre-symptomatic (preMH) patients; Number of GAC ≥ 40; GAP score ≥ 250; 10 ≤ TFC ≤ 13; TMS >5 if TFC=13; Diagnostic confidence level =4; Age onset of the disease > 20 years; Patients in physical capacity to sign the consent	Radiation: radiotracer injection; MRI with radiotracer injection
Active Comparator: Age-matched controls (healthy volunteers); TFC functional UHDRS score = 13; TMS engine UHDRS rating < 6	Radiation: radiotracer injection; MRI with radiotracer injection

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Genetic markers	Visit Month 0

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
cognitive tests	Cognitive scores - Neurological scores- Psychiatric scores	Visits Month 0, Month 1, Month 12, Month 24
biological markers	Neuroinflammation markers in blood - Neurodegeneration markers in blood	Visits Month 0, Month 1, Month 12, Month 24
multimodal imaging techniques	MRI	Visits Month 0, Month 12, Month 24
multimodal imaging techniques	PET/MRI	Visits Month 0, Month 24

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Study record dates

Study Major Dates

• Study Start (Estimated): January 17, 2024
• Primary Completion (Estimated): April 2, 2025
• Study Completion (Estimated): February 2, 2027

Study Registration Dates

• First Submitted: December 15, 2022
• First Submitted That Met QC Criteria: March 29, 2023
• First Posted (Actual): April 11, 2023

Study Record Updates

• Last Update Posted (Actual): January 17, 2024
• Last Update Submitted That Met QC Criteria: January 15, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Imaging; Cognition; Biomarkers; Disease progression; Huntington's disease
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Disease Attributes; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Disease Progression; Huntington Disease
• Other Study ID Numbers: APHP210360; 2021-004141-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No