IMarkHD: in Vivo Longitudinal Imaging of HD Pathology

NCT03434548 | Recruiting DMC

• 1 other identifier: IRAS 242859
• Study Type: observational
• Target: 113
• Locations: 1 country
• Sites: 1

Brief Summary

iMarkHD is an adaptive, longitudinal positron emission tomography (PET) and magnetic resonance (MR) imaging study in Huntington's disease (HD) that aims to assess abnormal molecular, functional, and structural changes in participants' brains, ranging from several years before symptom onset to the advanced symptom stage. The study will be conducted over a three (3) year period (Baseline, Year-1, and Year-2).

Conditions

Huntington Disease

Keywords

Huntington's disease; PET imaging; MRI imaging

Outcome Measures

Primary Outcomes (2)

• Primary outcome measure 1

  Quantitative change in binding profile of four discrete molecular PET markers over the period of 2 years. These markers include: 1. Cannabinoid 1 Receptor binding. 2. Phosphodiesterase 10A enzyme binding. 3. 5-hydroxytryptamine-2A receptor binding. 4. Histamine type-3 receptor binding. The study will assess basal ganglia and cortical pathology with four highly specific PET radioligands (\[11C\]MePPEP, \[11C\]IMA107, \[11C\]MDL100907 and \[11C\]MK-8278), tagging 4 targets of interest: cannabinoid type 1 receptors (CB1R), phosphodiesterase 10A (PDE-10A), 5-hydroxytryptamine-2A receptor (5-HT2AR) and histamine type-3 receptors (H3R), respectively, at baseline, 1 and 2years. The main focus will be on the basal ganglia.

  2 years

• Primary outcome measure 2

  Determine whether selected PET markers could be used as markers of HD disease progression and treatment response in therapeutic trials. These markers include: 1. Cannabinoid 1 Receptor binding. 2. Phosphodiesterase 10A enzyme binding. 3. 5-hydroxytryptamine-2A receptor binding. 4. Histamine type-3 receptor binding. The study will assess basal ganglia and cortical pathology with four highly specific PET radioligands (\[11C\]MePPEP, \[11C\]IMA107, \[11C\]MDL100907 and \[11C\]MK-8278), tagging 4 targets of interest: cannabinoid type 1 receptors (CB1R), phosphodiesterase 10A (PDE-10A), 5-hydroxytryptamine-2A receptor (5-HT2AR) and histamine type-3 receptors (H3R), respectively, at baseline, 1 and 2years. These outcomes will be linked to scale-based and other clinical outcomes performed over the same timelines to determine the link between clinically defined disease progression and the PET markers.

  2 years

Study Arms (2)

Cohort 1

Healthy controls. Multi-modal MRI imaging.

Other: Multi-modal MRI imaging

Cohort 2

People with Huntington's (without symptoms, early disease stage, and later disease stage), and healthy controls People with HD divided in groups according to disease stage: * Without symptoms (approximately HD-ISS stage 0 or 1) * Early disease (approximately HD-ISS stage 2) * Later disease stage (approximately HD-ISS stage 3)

Radiation: PET imaging; Other: Multi-modal MRI imaging

Interventions

PET imaging RADIATION

PET imaging Radiation: Radioligand \[¹¹C\]MePPEP Intravenous injection of radioligand in the arm with PET imaging of the brain. Radiation: Radioligand \[¹¹C\]IMA107 Intravenous injection of radioligand in the arm with PET imaging of the brain. Radiation: Radioligand \[¹¹C\]MDL100907 Intravenous injection of radioligand in the arm with PET imaging of the brain. Radiation: Radioligand \[¹¹C\]MDL100907 Intravenous injection of radioligand in the arm with PET imaging of the brain. PET imaging Radiation: Radioligand \[¹¹C\]MePPEP Intravenous injection of radioligand in the arm with PET imaging of the brain. Radiation: Radioligand \[¹¹C\]IMA107 Intravenous injection of radioligand in the arm with PET imaging of the brain. Radiation: Radioligand \[¹¹C\]MDL100907 Intravenous injection of radioligand in the arm with PET imaging of the brain. Radiation: Radioligand \[¹¹C\]MDL100907 Intravenous injection of radioligand in the arm with PET imaging of the brain.

Cohort 2

Multi-modal MRI imaging OTHER

Multi-modal MRI imaging

Cohort 1; Cohort 2

Eligibility Criteria

• Age: 21 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

People with Huntington's disease (PwHD) and healthy controls (HCs). PwHD participants will be recruited from specialty clinics known as Participant Identification Centers (Human Genetics, Neurology, Psychiatry) that advise and treat people affected by HD. Participants may receive information about the study through a website, clinical practices, advocacy newsletters, or other approved sources. Community controls will be recruited using advertisements, flyers, and newsletters with the support of the iMarkHD operational staff.

You may qualify if:

• PwHDs and HC participants:
• Female and male adults, aged 21-75 years old, inclusive.
• Adequate visual (Snellen chart) and auditory (Rinne and Weber tests) acuity to complete the psychological testing as determined by the investigator.
• Capable of giving informed consent.
• Willing to comply with highly effective contraceptive measures following informed consent (for Cohort 2 only).
• Vital signs within certain set ranges.
• Considered by the investigator to be in good health as judged by the absence of clinically significant diseases, laboratory values, physical examination, and able to travel to imaging and clinical assessment centers in London, UK.
• Suitable physically and psychologically to travel (with a companion if requested) and undergo the assessments as judged by the investigator.
• PwHDs without symptoms: (approximately HD-ISS stage 0 or 1)
• HDGECs with ≥ 40 CAG repeats
• TMS ≤ 6 AND TFC ≥ 12 AND CAP \> 70 PwHDs with symptoms in early disease: (approximately HD-ISS stage 2)
• HDGECs with ≥ 40 CAG repeats
• If one of the following criteria is met:
• TMS ≤ 6 AND TFC = 11
• TMS is between 7 and 23 inclusive AND TFC is between 11 and 13 inclusive

You may not qualify if:

• PwHD and HC participants:
• Presence or history of other neurological condition (including brain surgery, intracranial hematoma, stroke/cerebrovascular disorders, demyelinating conditions, epilepsy) likely to interfere with imaging or PET studies or abnormal neurologic examination finding suggestive of a central nervous system pathology (for PwHDs - other than HD).
• Presence or history of primary psychiatric disorders unrelated to HD.
• Participants using any medications with known actions on cannabinoid type 1 receptors (CB1R), phosphodiesterase 10A (PDE-10A), 5-hydroxytryptamine-2A receptor (5-HT2AR), histamine type-3 receptors (H3R), or any other PET targets used in iMarkHD.
• Pregnancy confirmed by a positive urine pregnancy test.
• Participants who are currently breastfeeding or intend to breastfeed during the study.
• Contraindication to MRI, such as presence of metal devices or implants (e.g. pacemaker, vascular- or heart- valves, stents, clips), metal deposited in the body (e.g. bullets or shells), or metal grains in the eyes.
• History of alcoholism or substance abuse within 3 years prior to study entry.
• Failure of drug screen for substances of abuse such as amphetamines, barbiturates, benzodiazepines, methadone, opiates, cocaine, cannabinoids, phencyclidine, and creatine.
• History of cancer.
• Claustrophobia.
• Significant back pain that makes prolonged laying on the PET or MRI scanner intolerable.
• Contraindication for arterial cannulation as judged by the Allen test and the laboratory blood screening for coagulopathy (Cohort 2 only).
• Inability to communicate or cooperate with the principal investigator/iMarkHD team for any reason.
• Participants who are currently enrolled in or participated in clinical trials testing the efficacy of novel therapeutics with action on the specific PET targets being tested within 3 months of screening.

Sponsors & Collaborators

• King's College London: lead
• CHDI Foundation, Inc.: collaborator

Study Sites (1)

King's College London

London, England, SE5 8AF, United Kingdom

RECRUITING

Biospecimen

Retention: SAMPLES WITHOUT DNA

Analysis will be performed to confirm the size of the CAG expansion mutation within the HD gene for all PwHD, for research purposes only.

MeSH Terms

Conditions

Huntington Disease

Interventions

Magnetic Resonance Spectroscopy

Condition Hierarchy (Ancestors)

Basal Ganglia Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Dementia; Chorea; Dyskinesias; Movement Disorders; Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Spectrum Analysis; Chemistry Techniques, Analytical; Investigative Techniques

Study Officials

• Steve Williams, PhD

  King's College London

  STUDY CHAIR

• Daniel J van Wamelen, PhD

  King's College London

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Steve Williams, PhD

CONTACT

0044-(0)-203-228-3063; steve.williams@kcl.ac.uk

Daniel J van Wamelen, PhD

CONTACT

0044-(0)-203-228-3084; daniel.van_wamelen@kcl.ac.uk

Study Design

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

Study Record Dates

• First Submitted: February 7, 2018
• First Posted: February 15, 2018
• Study Start: July 20, 2021
• Primary Completion (Estimated): June 30, 2027
• Study Completion (Estimated): June 30, 2027
• Last Updated: March 5, 2025

Record last verified: 2025-03

Locations

GB (1)