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Trial record 16 of 152 for:    HTT

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

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ClinicalTrials.gov Identifier: NCT03810898
Recruitment Status : Not yet recruiting
First Posted : January 21, 2019
Last Update Posted : January 21, 2019
Sponsor:
Collaborators:
Karolinska Institutet
Universitaire Ziekenhuizen Leuven
Information provided by (Responsible Party):
CHDI Foundation, Inc.

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.


Condition or disease Intervention/treatment Phase
Huntington Disease Radiation: Radioligand [¹¹C]CHDI-00485180-R Radiation: Radioligand [¹¹C]CHDI-00485626 Early Phase 1

Detailed Description:

The study investigators have developed two novel PET radioligands that will be evaluated for their suitability for use in clinical research settings to quantify mHTT in HDGECs. The PET radioligands do not have any pharmacological effect at the microdoses (total dose <100ug) at which they will be administered; they will not be administered at pharmacological doses. This study has a modular design in two phases, and each phase will enroll a small independent cohort. The execution of each subsequent phase is dependent on results from the previous phase.

Phase 1 is the initial evaluation of the PET radioligands. A suitable PET radioligand is expected to produce quantifiably higher binding in HD participants' brains compared to young HC participants' brains (since they do not express mHTT). Phase 1 is divided in two sub phases: Phase 1a will evaluate the basic safety and kinetic properties as well as brain uptake in three (3) young HCs; Phase 1b will test the difference in binding in six (6) HDGECs with Stage II HD compared to six (6) young HCs (three (3) young HCs will be imaged in addition to the three (3) young HCs from 1a. The rationale behind using young HCs in Phase 1 is to screen out HC participants who may have undiagnosed amyloid-β (Aβ) plaques, a potential off-target binding site for [¹¹C]CHDI-00485180-R. The rationale behind imaging HDGECs with Stage II HD in Phase 1 is based on the hypothesis that the density of mHTT aggregates increases with disease severity, and the ability to detect a difference in binding between HCs and HDGECs is expected to be higher in Stage II HD (more severe stages of HD will not be included in this study). An option to image three (3) pre-manifest HDGECs from Phase 2c (see below) will be included in case the results indicate that brain atrophy (i.e., loss of aggregate due to atrophy) affects the binding and evaluation of the PET radioligands in HDGECs with Stage II HD. For each of the two PET radioligands a Go/ No-Go evaluation will take place (for overview see Figure 1); if satisfactory results are not obtained for a particular radioligand, then that radioligand will not progress to evaluation in further phases. Promising results for either radioligand will lead to that particular radioligand continuing to Phase 2 evaluation.

Phase 2 will evaluate the sensitivity of the PET radioligand(s) to discriminate between different stages and severity of HD. In addition, a TRT in Phase 2 will evaluate the variability of repeated imaging for the PET radioligand. Phase 2 has a sequential design in sub phases that will assess the sensitivity of the radioligand in descending severity of HD: 2a in six (6) HDGECs with Stage II HD and six (6) age-matched controls; 2b in six (6) HDGECs with Stage I HD and six (6) age-matched controls; 2c in six (6) premanifest HDGECs and six (6) age-matched controls. The rationale for imaging groups of descending HD severity is based on the hypothesis that the density of mHTT aggregates increases with disease severity, and the ability to detect a difference in binding between HCs and HDGECs is expected to be lowest in the premanifest stage. This design will enable a stepwise assessment of the sensitivity of the PET radioligands. After each sub-phase a Go/No-Go evaluation will take place; if satisfactory results are not obtained for a particular radioligand then that radioligand will not be evaluated in further sub-phases. Promising results for either radioligand will lead to that particular radioligand continuing to the next sub-phase.

This study design allows each radioligand to be reviewed and analyzed after evaluation in each cohort. The progression through each level of analysis will indicate whether either or both radioligands will measure mHTT aggregate levels with sufficient sensitivity to become potential disease progression and efficacy biomarker(s) in HDGECs.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 84 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Huntington's disease gene expansion carriers (HDGEC) compared to healthy controls (HC)
Masking: None (Open Label)
Primary Purpose: Other
Official Title: First-in-Human Adaptive Study to Investigate the Binding and Kinetic Properties of Two Novel PET Ligands and Their Suitability for Quantification of Aggregated Mutant Huntingtin in the Brains of Huntington's Disease Gene-Expansion Carriers
Estimated Study Start Date : May 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Phase 1 (a & b)

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

Radiation: Radioligand [¹¹C]CHDI-00485626
Intravenous injection of radioligand in the arm with PET imaging of the brain.

Experimental: Phase 2a

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

Radiation: Radioligand [¹¹C]CHDI-00485626
Intravenous injection of radioligand in the arm with PET imaging of the brain.

Experimental: Phase 2b

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

Radiation: Radioligand [¹¹C]CHDI-00485626
Intravenous injection of radioligand in the arm with PET imaging of the brain.

Experimental: Phase 2c

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

Radiation: Radioligand [¹¹C]CHDI-00485626
Intravenous injection of radioligand in the arm with PET imaging of the brain.




Primary Outcome Measures :
  1. The VT (volume of distribution total) of 2 discrete PET markers will be measured with PET imaging. [ Time Frame: Single point measure- 90 minutes scan ]
    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).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   20 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

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 Stockholm, Sweden or 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 ≥ 36; and
  • Have Stage I HD, defined as UHDRS Total Functional Capacity (TFC) scores between 11 and 13 inclusive.

HDGECs with Stage II HD:

  • Have clinical diagnostic motor features of HD, defined as UHDRS Diagnostic Confidence Score = 4; and
  • Have CAG expansion ≥ 36; and Have Stage II HD, defined as UHDRS Total Functional Capacity (TFC) scores between 7 and 10 inclusive.

HC participants:

  • Have 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).
  • Matched by age +/- 5 years.
  • (Phase 1 only) under 35 years of age.

Exclusion Criteria:

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.
  • 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:

  • Previous participation in PET imaging study that, cumulatively with the current study, will exceed annual regulatory limits for radiation exposure.
  • 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:

  • Previous participation in PET studies.
  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03810898


Contacts
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Contact: Illona Feldman 609-945-9629 illona.feldman@chdifoundation.org

Locations
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Belgium
Universitaire Ziekenhuizen Leuven/ UZ Lueven/ UZL Not yet recruiting
Leuven, Belgium, 3000
Contact: Wim Vandenberghe, MD, PhD    32 16344280    wim.vandenberghe@uzleuven.be   
Contact: Koen Van Laere, MD, PhD, DSc    32 16 34 37 11    koen.vanlaere@uzleuven.be   
Principal Investigator: Wim Vandenberghe, MD, PhD         
Sub-Investigator: Koen Van Laere, MD, PhD, DSc         
Sweden
Karolinska University Hospital Not yet recruiting
Stockholm, Sweden, SE-171 76
Contact: Malena Kjellen, RN    +070-735-0835    malena.kjellen@ki.se   
Principal Investigator: Andrea Varrone, MD, PhD         
Sub-Investigator: Patrik Fazio, MD         
Sponsors and Collaborators
CHDI Foundation, Inc.
Karolinska Institutet
Universitaire Ziekenhuizen Leuven
Investigators
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Principal Investigator: Andrea Varrone, MD, PhD Karolinska Institutet
Study Director: Mette Skinbjerg, PhD CHDI Management/ CHDI Foundation

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Responsible Party: CHDI Foundation, Inc.
ClinicalTrials.gov Identifier: NCT03810898     History of Changes
Other Study ID Numbers: C-000418-2
First Posted: January 21, 2019    Key Record Dates
Last Update Posted: January 21, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by CHDI Foundation, Inc.:
huntingtin
Huntington Disease
Huntington's Disease
HD
HDGEC
Gene Expansion Carrier
PET
Tracer
Positron Emission Tomography
radioligand
imaging
mHTT
iMagemHTT

Additional relevant MeSH terms:
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Huntington Disease
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
Cognition Disorders
Neurocognitive Disorders
Mental Disorders