Clinical Study to Monitor Plasma Levels of 24OHC in Subject With HD (Chol-HD)

Innovative Therapeutic Strategy Targeting Neurons With Cholesterol in Huntington Disease: From Preclinical Studies to Clinical Trial Readiness

A 2-year clinical longitudinal study to measure plasma concentrations of 24S-hydroxycholesterol, a brain-derived cholesterol catabolite, in subjects with Huntington disease, from the presymptomatic to the symptomatic stages.

Study Overview

• Status: Recruiting
• Conditions: Huntington Disease
• Intervention / Treatment: Diagnostic test: Brain MRI

Detailed Description

In cross-sectional studies, the plasma level of brain-derived 24S-hydroxycholesterol (24OHC) has been found to be significantly diminished in HD patients from the first stages of the disease. Furthermore, in HD gene-positive pre-symptomatic (pre-HD) the plasma levels can predict the development of motor signs of disease in subjects closer to onset, better than in subjects far from onset. These data suggest that circulating 24OHC might be a candidate biomarker for phenotypic conversion and for disease progression in different stages of the disease.

Detailed neurological, cognitive and imaging data and blood samples will be collected at baseline, and after two years to investigate the rate of changes along the longitudinal study. Isotope dilution mass spectrometry (assay performed at Istituto di Ricerche Farmacologiche Mario Negri IRCCS) will be used to measure the plasma levels of brain-derived 24OHC and other sterols reflecting peripheral cholesterol synthesis. The investigators expect to establish whether changes in plasma 24OHC mark disease progression and, eventually, phenoconversion from pre-symptomatic to symptomatic stages in combination with clinical, cognitive and imaging parameters.

• Study Type: Observational
• Enrollment (Anticipated): 60

Contacts and Locations

• Study Contact: Name: Renato Mantegazza, MD; Phone Number: 2321 +39022394; Email: crc@istituto-besta.it
• Study Contact Backup: Name: Caterina Mariotti, MD; Phone Number: 2269 +39022394; Email: caterina.mariotti@istituto-besta.it

Study Locations

• Italy
  • Milano, Italy, 20133
    • Recruiting
    • UOC Genetica Medica e Neurogenetica
    • Principal Investigator: Caterina Mariotti, MD
    • Sub-Investigator: Lorenzo Nanetti, MD
    • Contact: Caterina Mariotti, MD; Phone Number: 2269 +39022394; Email: caterina.mariotti@istituto-besta.it
    • Contact: Lorenzo Nanetti, MD; Phone Number: 2519 +39022394; Email: lorenzo.nanetti@istituto-besta.it
    • Sub-Investigator: Alessia Mongelli, Msc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

At least 60 subjects (both males and females) will be enrolled in the study. Eligible participants include healthy controls, people who are in the presymptomatic stage of HD, and people with symptomatic HD at different disease stage (I-III).

Description

Inclusion Criteria:

Symptomatic HD subjects

1. Age ≥ 18 years
2. Known family history of HD and genetically confirmed disease by direct DNA test (CAG expansion > 35 repeats)
3. Clinical diagnostic motor features of HD, defined as score> 5 at the motor Unified Huntington Disease Rating Scale (mUHDRS)
4. Stage I or II or III HD, defined as UHDRS Total Functional Capacity (TFC) scores between 3 and 13 inclusive (Marder, 2000)

Presymptomatic HD subjects

1. Age ≥ 18 years
2. Known family history of HD and genetically confirmed mutation by direct DNA test (CAG expansion > 35 repeats)
3. Absence of clinical motor features of HD, defined as mUHDRS rating scale ≤ 5

Healthy Subjects

1. Age ≥ 18 years
2. Absence of known family history of HD or genetically confirmed negative DNA test for HD (CAG expansion ≤ 35 repeats)
3. Absence of clinical motor features of HD, defined as mUHDRS rating scale ≤ 5

Exclusion Criteria:

1. Participation in clinical pharmacological trials
2. Inability to undergo and tolerate MRI scans (e.g. claustrophobia, severe chorea, MRI-incompatible intrauterine devices, metal implants, ect)
3. Inability or unwillingness to undertake any of the study procedures

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy controls subjects; Subjects without known family history of HD, or tested negative for the HD expansion mutation.	Diagnostic test: Brain MRI; Neurological and Cognitive evaluation; Brain MRI
Symptomatic HD subjects; Subjects HD gene expansion carriers who have clinical diagnostic motor symptoms of defined HD, and disease stage I to III.	Diagnostic test: Brain MRI; Neurological and Cognitive evaluation; Brain MRI
Presymptomatic HD subjects: Subjects HD gene expansion carriers who not have clinical diagnostic motor features of HD.	Diagnostic test: Brain MRI; Neurological and Cognitive evaluation; Brain MRI

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
plasmatic 24OHC levels	Changes in plasmatic 24OHC levels measured	at baseline and after 2-years follow up visit

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes in the score of the Unified Huntington Disease Rating Scale (UHDRS)	The concentration of 24OHC will be correlated with clinical evaluation to the stage of the disease and its progression.	after 2-years follow up visit
Changes in score at the Digit Symbol Modalities Test (DSMT)	The concentration of 24OHC will be correlated with cognitive evaluation to the stage of the disease and its progression.	after 2-years follow up visit
Changes in caudate nucleus volume measured at MRI	The concentration of 24OHC will be correlated with Imaging the stage of the disease and its progression.	after 2-years follow up visit

Collaborators and Investigators

• Sponsor: Fondazione I.R.C.C.S. Istituto Neurologico Carlo Besta
• Collaborators: Istituto Di Ricerche Farmacologiche Mario Negri

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2019
• Primary Completion (Anticipated): September 1, 2021
• Study Completion (Anticipated): September 1, 2022

Study Registration Dates

• First Submitted: January 31, 2020
• First Submitted That Met QC Criteria: February 3, 2020
• First Posted (Actual): February 6, 2020

Study Record Updates

• Last Update Posted (Actual): February 10, 2021
• Last Update Submitted That Met QC Criteria: February 9, 2021
• Last Verified: February 1, 2021

More Information

Terms related to this study

• Keywords: Cholesterol; Huntington Disease
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Genetic Diseases, Inborn; Basal Ganglia Diseases; Movement Disorders; Neurodegenerative Diseases; Dyskinesias; Heredodegenerative Disorders, Nervous System; Dementia; Cognition Disorders; Chorea; Huntington Disease
• Other Study ID Numbers: Chol-HD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

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