iMagemHTT: FIH Evaluation of Novel Mutant Huntingtin PET Radioligands [¹¹C]CHDI-00485180-R and [¹¹C]CHDI-00485626

NCT03810898 | Terminated Early Phase 1

• 1 other identifier: C-000418-2
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

This is a FIH (first-in-human) adaptive PET (Positron Emission Tomography) imaging study to explore the binding and kinetic properties of two potential mutant huntingtin (mHTT) radioligands; \[¹¹C\]CHDI-00485180-R and \[¹¹C\]CHDI-00485626. The binding characteristics of these radioligands will be evaluated first in young (\< 35 years of age) healthy control (HC) participants (Phase 1a) and subsequently in young HCs and Huntington's disease gene-expansion carriers (HDGECs) with Stage II HD (Phase 1b). Subsequent phases will continue to explore the radioligands' binding characteristics in HDGECs with Stage II HD (Phase 2a), Stage I HD (Phase 2b) and pre-manifest HDGECs (Phase 2c) and their age matched healthy controls. All phases are cross-sectional and will include comparisons between HCs and HDGECs. Test-retest (TRT) evaluations will be done during Phase 2a, with the option of including further test-retests in Phases 2b, and 2c after review of data by the iMagemHTT Executive Committee. TRT is only applicable to HDGEC participants. There are four planned interim analyses at which either radioligand may be dropped if its characteristics are shown to be suboptimal. If successful, the study will establish \[¹¹C\]CHDI-00485180-R and/or \[¹¹C\]CHDI-00485626 as fit for further development as drug development tools to measure mHTT levels in HDGECs. This development is intended to demonstrate the value of PET imaging with these radioligands as a disease progression biomarker, predictive biomarker, pharmacodynamic biomarker, and eventually as an efficacy biomarker. All HDGEC participants will be invited to provide an optional cerebrospinal fluid (CSF) sample that will be collected after the imaging visits are complete. These samples will be processed to evaluate CSF mHTT levels and other potential biomarkers and to explore potential relationships between soluble CSF mHTT levels and mHTT binding identified by \[¹¹C\]CHDI-00485180-R and/or \[¹¹C\]CHDI-00485626 PET imaging. Potential CSF biomarkers that might be co-expressed or accumulated in HD may also be examined.

Conditions

Huntington Disease

Keywords

Huntington Disease; Huntington's Disease; HD; HDGEC; Gene Expansion Carrier; PET; Tracer; Positron Emission Tomography; radioligand; imaging; mHTT; huntingtin; iMagemHTT

Outcome Measures

Primary Outcomes (1)

• The VT (volume of distribution total) of 2 discrete PET markers will be measured with PET imaging.

  VT (volume of distribution total) is derived from the data collected during each PET scan. VT is the amount of the PET marker in a volume of tissue (i.e., a concentration).

  Single point measure- 90 minutes scan

Study Arms (4)

Phase 1 (a & b)

EXPERIMENTAL

Radioligand \[¹¹C\]CHDI-00485180-R and/or Radioligand \[¹¹C\]CHDI-00485626/ 6 Stage II HDGECs and 6 young (\< 35) HCs/ Imaging- MRI and PET/ Both radioligands administered- 1x each/ Optional CSF collection for HDGECs

Radiation: Radioligand [¹¹C]CHDI-00485180-R; Radiation: Radioligand [¹¹C]CHDI-00485626

Phase 2a

EXPERIMENTAL

Per Radioligand- Radioligand \[¹¹C\]CHDI-00485180-R or Radioligand \[¹¹C\]CHDI-00485626/ 6 Stage II HDGECs and 6 age matched HCs/ Imaging- MRI and PET/ 1 Radioligand administered 2x (test re-test)- HDGECs/ Optional CSF collection for HDGECs 1 Radioligand administered 1x- HCs/

Radiation: Radioligand [¹¹C]CHDI-00485180-R; Radiation: Radioligand [¹¹C]CHDI-00485626

Phase 2b

EXPERIMENTAL

Per Radioligand- Radioligand \[¹¹C\]CHDI-00485180-R or Radioligand \[¹¹C\]CHDI-00485626/ 6 Stage I HDGECs and 6 age matched HCs/ Imaging- MRI and PET/ 1 Radioligand 1 or 2x administered (test re-test optional)- HDGECs/ Optional CSF collection for HDGECs 1 Radioligand administered 1x -HCs/

Radiation: Radioligand [¹¹C]CHDI-00485180-R; Radiation: Radioligand [¹¹C]CHDI-00485626

Phase 2c

EXPERIMENTAL

Per Radioligand- Radioligand \[¹¹C\]CHDI-00485180-R or Radioligand \[¹¹C\]CHDI-00485626/ 6 Pre-manifest HDGECs and 6 age matched HCs/ Imaging- MRI and PET/ 1 Radioligand administered 1 or 2x (test re-test optional)- HDGECs/ Optional CSF collection for HDGECs 1 Radioligand administered 1x- HCs/

Radiation: Radioligand [¹¹C]CHDI-00485180-R; Radiation: Radioligand [¹¹C]CHDI-00485626

Interventions

Radioligand [¹¹C]CHDI-00485180-R RADIATION

Intravenous injection of radioligand in the arm with PET imaging of the brain.

Phase 1 (a & b); Phase 2a; Phase 2b; Phase 2c

Radioligand [¹¹C]CHDI-00485626 RADIATION

Intravenous injection of radioligand in the arm with PET imaging of the brain.

Phase 1 (a & b); Phase 2a; Phase 2b; Phase 2c

Eligibility Criteria

• Age: 20 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Pre-manifest HDGECs, HDGECs with Stage I HD, HDGECs with Stage II HD and HC participants:
• Female and male adults, age 20-65 years old, inclusive.
• Body Mass Index (BMI) between 19 and 35 inclusive.
• Capacity to give full informed consent in writing, and have read and signed the informed consent form (ICF).
• Are capable of complying with study procedures, including fasting and blood sampling
• Able and willing to travel to imaging PET center in Leuven, Belgium.
• Willing to comply with the use of adequate contraceptive measures.
• Pre-manifest HDGECs:
• Do not have clinical diagnostic motor features of HD, defined as Unified Huntington's Disease Rating Scale (UHDRS) Diagnostic Confidence Score \< 4; and
• Have CAG expansion ≥ 40; and
• Have a CAP score \> 70 (as calculated with CAP formula: AGE \* (CAG - 30) / 6.49).
• HDGECs with Stage I HD:
• Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic Confidence Score = 4; and
• Have CAG expansion ≥ 40; and
• Have Stage I HD, defined as UHDRS Total Functional Capacity (TFC) scores between 11 and 13 inclusive.

You may not qualify if:

• Pre-manifest HDGECs, HDGECs with Stage I HD, HDGECs with Stage II HD, and HC participants:
• Currently participating in or less than 30 days after completing participation in other therapeutic or imaging studies.
• Previous participation in PET imaging study that, cumulatively with the current study, will exceed annual regulatory limits for radiation exposure.
• Any disease, condition, or concomitant medication that significantly compromises the function of the body systems and that in the opinion of the Investigator, might interfere with the conduct of the study or its interpretation.
• Pregnant and breastfeeding females.
• Concomitant medication (ConMed) use of antiplatelet or anticoagulant therapy (inclusive of acetylsalicylic acid). (See full ConMed list attached.)
• Needle phobia.
• HDGEC participants:
• If using any antidepressant, psychoactive, psychotropic or other medications or nutraceuticals used to treat HD, the use of inappropriate (e.g., non-therapeutically high) or unstable dose within 30 days prior to participation.
• HC participants:.
• Family history of HD (unless genetic test confirming negative results).
• For participants in optional CSF sample collection:
• Frequent headache, significant lower spinal deformity or major surgery; or
• Bleeding disorder.

Sponsors & Collaborators

• CHDI Foundation, Inc.: lead
• Universitaire Ziekenhuizen KU Leuven: collaborator

Study Sites (1)

Universitaire Ziekenhuizen Leuven/ UZ Leuven/ UZL

Leuven, 3000, Belgium

Location

Related Publications (1)

• Delva A, Koole M, Serdons K, Bormans G, Skinbjerg M, Khetarpal V, Liu L, Bard J, Doot R, Warner JH, Sathe S, Sampaio C, Wood A, Van Laere K, Vandenberghe W. PET imaging with [(1)(1)C]CHDI-00485180-R, designed as radioligand for aggregated mutant huntingtin, in people with Huntington's disease. Eur J Nucl Med Mol Imaging. 2025 Nov;52(13):5124-5134. doi: 10.1007/s00259-025-07394-w. Epub 2025 Jun 18.

  PMID: 40527969 DERIVED

MeSH Terms

Conditions

Huntington Disease

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

Study Officials

• Wim Vandenberghe, MD, PhD

  Universitaire Ziekenhuizen Leuven/ UZ Leuven/ UZL

  PRINCIPAL INVESTIGATOR

• Mette Skinbjerg, PhD

  CHDI Management/ CHDI Foundation

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Huntington's disease gene expansion carriers (HDGEC) compared to healthy controls (HC)

Study Record Dates

• First Submitted: December 7, 2018
• First Posted: January 22, 2019
• Study Start: February 9, 2021
• Primary Completion: February 15, 2023
• Study Completion: February 15, 2023
• Last Updated: May 6, 2023

Record last verified: 2023-05

Locations

BE (1)