iMarkHD

Recruiting

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SPONSOR

Kings College London

PARTICIPANTS

113

The study has two main golas using 2 types of brain scans.

First,  using a series of PET scans to investigate 4 target receptors in specific areas of the brain that are affected by HD and are thought to be responsible for the motor, cognitive, and behavioural symptoms.

Second, to look at  changes in struture and function including alterations in brain connections, using MRI scans

The investigators will compare PET and MRI measurements at different disease stages with age- and sex-matched healthy control (HC) participants. They will look at how specific or combination of changes may influence the development of symptoms and disease progression. The hope would be identify disease progression markers that can  predict events before symptom development. This could be used as outcome measures in future clinical trials. Study results could also lead to the development of new targeted therapies.

This is a longitudinal study  done  over a 3  year period (Baseline, Year-1, and Year-2).

Subtype: Observational Biomarker
Intervention Type: radiation
Primary Intervention: PET markers

Ages Eligible
for Study:

18 to 75 Years and older

(Adult, Older Adult)

Sexes Eligible
for Study:

All

Accepts Healthy Volunteers:

Yes

  • 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:

      1. TMS ≤ 6 AND TFC = 11
      2. TMS is between 7 and 23 inclusive AND TFC is between 11 and 13 inclusive
      3. TMS is between 24 and 33 inclusive AND SDMT > 50 AND TFC is between 11 and 13 inclusive PwHDs with symptoms in late disease (approximately HD-ISS stage 3)
    • HDGECs with ≥ 40 CAG repeats
    • If one of the following criteria is met:

      1. TMS ≤ 6 AND TFC is between 7 and 10 inclusive
      2. TMS is between 7 and 23 inclusive AND TFC is between 8 and 10 inclusive
      3. TMS is between 24 and 33 inclusive AND SDMT > 50 AND TFC is between 7 and 10 inclusive
      4. TMS is between 7 and 23 inclusive AND TFC = 7
      5. TMS > 23 AND SDMT ≤ 50 AND TFC is between 7 and 13 inclusive
      6. TMS > 33 AND SDMT > 50 AND TFC is between 7 and 13 inclusive

    Healthy Controls (HC):

    • Age- and sex-matched, and balanced (±8 years) with PwHDs.
    • No known family history of HD or have known family history of HD but have been tested for the huntingtin gene glutamine codon (CAG) expansion and are not at genetic risk for HD (CAG < 36).

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.
  • Any concurrent conditions that could interfere with the safety and/or tolerability measurements.

LOCATION

UNITED KINGDOM

TRIAL SITE:
Kings College London

Address: London, UK

CONTACT
Daniel J van Wamelen, PhD
Email:daniel.van_wamelen@kcl.ac.uk

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oxidative seres

an imbalance between unstable molecules called “free radicals” and protective “antioxidants” in your body

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Metabolism & bioenergetics

describe how your body turns food into fuel and uses that energy to live. 

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Small Molecule

a tiny chemical compound, much smaller than big biological structures like proteins, that can easily travel inside our cells to act as medicine (like aspirin or ibuprofen), a building block (like glucose), or a signaling tool in the body, often taken as pills because they’re easy to absorb and distribute

 

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Nucleic acid

(DNA and RNA) are the essential information-carrying molecules in all life, acting like blueprints that store and transmit genetic instructions for building and operating cells, directing everything from growth to protein production, and passing traits from parents to offspring.

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SNP-single nucleotide polymorphisms

a single-letter spelling difference in a gene. SNPs, pronounced ‘snips’, are common and most don’t change the function of the gene.

 
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at risk

You do not know if you carry the genetic mutation for HD gene 

 
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TFC-total functional capacity

A standardized rating scale for function in HD, used to assess capacity to work, handle finances, perform domestic chores and self-care tasks.
Scores range from 0 to 13, with higher scores indicating better functional capacity. 

 
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Double-blinded

 means that neither the participant nor the clinical trial doctor can choose or know the group the participant is in until the trial is over. This approach helps to prevent bias.

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Open label

A trial in which the patient and doctor know what drug is being used. Open label trials are susceptible to bias through placebo effects.

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Gene therapy

a technique that aims to treat or prevent diseases by modifying a person’s genes. It involves introducing, removing, or changing genetic material (DNA or RNA) within a patient’s cells.

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UHDRS- Unified Huntington Disease Rating Scale

A standardized neurological examination that aims to provide a uniform assessment of the clinical features of HD

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CAG repeat

The stretch of DNA at the beginning of the HD gene, which contains the sequence CAG repeated many times, and is abnormally long in people who will develop HD

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Wild-type

the opposite of ‘mutant’. Wild-type huntingtin, for example, is the ‘normal’, ‘healthy’ protein

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Tolerabilty

How well a person can handle a treatment without having serious or uncomfortable side effects.

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Striatum

Part of the brain that  coordinates multiple aspects of cognition, including both motor and action planning, decision-making, motivation, reinforcement, and reward system.

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Randomized allocation

A type of allocation strategy in which participants are assigned to the arms of a clinical trial by chance.

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Radioligand

a radioactive substance that binds to a specific target in the body, allowing visualization of that target’s distribution and activity

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Protein

Protein builds, maintains, and replaces the tissues in your body. The building blocks of life.

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Premanifest / Prodromal

Prior to onset or diagnosis of movement symptoms.

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Placebo

A placebo is a dummy medicine containing no active ingredients. The placebo effect is a psychological effect that causes people to feel better even if they’re taking a pill that doesn’t work.

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PK - Pharmacokinetics

The movement of drugs through the body

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PD - Pharmacodynamics

The body’s biological response to drugs

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PET scan

Positron emission tomography which produces detailed 3-dimensional images of the inside of the body.

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Neuron

Brain cells that store and transmit information

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MRI

Magentic resonance imaging: A technique using powerful magnetic fields to produce detailed images and visualizes the structure of organs, tissues, and bones 

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mHTT

Mutant huntingtin protein. The protein produced by the faulty HD gene.

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Manifest

after HD diagnosis, or when symptoms are already showing

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Longitudinal study

A study where each participant is looked at several times over a time period – unlike a cross-sectional study, where each participant is looked at only once

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HTT

one abbreviation for the gene that causes Huntington’s disease. The same gene is also called HD and IT-15

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fMRI

functional MRI:As with MRI, a technique using powerful magnetic fields  but focusing on brain function by measuring and mapping changes in blood flow, revealing which areas of the brain are active during specific tasks or cognitive processes

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CSF - cerebrospinal fluid

A clear fluid produced by the brain, which surrounds and supports the brain and spinal cord.

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Efficacy

A measure of whether a treatment works or not

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ASO(Antisense oligonucleotides)

A type of gene silencing treatment in which specially designed DNA molecules are used to switch off a gene

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Biomarker

a test of any kind – including blood tests, thinking tests and brain scans – that can measure or predict the progression of a disease like HD. Biomarkers may make clinical trials of new drugs quicker and more reliable

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BDNF

Brain-derived neurotrophic factor: a growth factor that may be able to protect neurons in HD.

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Allele

one of the two copies of a gene

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Plasma

Liquid component of the blood.

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Gene

The basic unit of heredity passed from parent to child. Genes are made up of sequences of DNA and are arranged, one after another, at specific locations on chromosomes in the nucleus of cells.

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Phase

Clinical trial phases are different stages of research that assess the safety and effectiveness of a new medical treatment or intervention in humans.

Each phase has a specific goal and involves a different number of participants. Generally, there are 4 phases (I-IV), with Phase I focusing on safety and dosage, Phase II on efficacy and side effects, Phase III on comparing the new treatment with standard treatments, and Phase IV on long-term safety monitoring.