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Safety and Tolerability Study With VY-HTT01, in Adults With Early Manifesting Huntington's Disease

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ClinicalTrials.gov Identifier: NCT04885114
Recruitment Status : Withdrawn (We have discontinued our 1st generation HD program with the VYTAL Study & have initiated a 2nd generation program using a novel, proprietary AAV capsid that may enable intravenous administration & achieve widespread distribution to affected tissue.)
First Posted : May 13, 2021
Last Update Posted : August 16, 2021
Sponsor:
Information provided by (Responsible Party):
Voyager Therapeutics

Study Description
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Brief Summary:
This is the first clinical study of VY-HTT01, a gene therapy for early-stage Huntington's Disease (HD) patients. The primary goal of this trial is to evaluate the safety and tolerability of VY-HTT01. This study is a first in human study, Phase 1b, open-label, randomized, multicenter, dose escalation study with a delayed treatment control arm.

Condition or disease Intervention/treatment Phase
Huntington Disease Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT Phase 1

Detailed Description:
This dose escalation trial will evaluate the safety and tolerability of 4 single dose levels of VY-HTT01. The maximum duration that a subject randomized to treatment may be involved in the study is up to 15 months. Delayed treatment subjects will be followed for a minimum of 6 months as a control before moving up into the treatment arm in the next cohort. The maximum duration that a delayed treatment subject may be involved in the study is up to 24 months. Subjects who participate in this study will be asked to enroll in a long-term observation study.
Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 0 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1B, Open-label, Randomized, Controlled, Multicenter, Dose Escalation Study of the Safety, Tolerability, and Biological Effects of VY-HTT01 Administered Via Intraparenchymal Infusion of the Putamen and Thalamus in Adults With Huntington's Disease
Estimated Study Start Date : July 30, 2021
Estimated Primary Completion Date : December 30, 2024
Estimated Study Completion Date : December 30, 2024

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1 Unilateral low dose
3.0 x 10^9 (vg/mL) rAAV1-miHHT
 Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT
Single dose MRI guided intraparenchymal infusion of rAAV1 - (mi)RNA HTT.
Other Name: VY-HTT01
Experimental: Cohort 2 Bilateral low dose
3.0 x 10^9 (vg/mL) rAAV1-miHHT
 Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT
Single dose MRI guided intraparenchymal infusion of rAAV1 - (mi)RNA HTT.
Other Name: VY-HTT01
Experimental: Cohort 3 Bilateral mid dose
1.7 x 10^10 (vg/mL) rAAV1-miHHT
 Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT
Single dose MRI guided intraparenchymal infusion of rAAV1 - (mi)RNA HTT.
Other Name: VY-HTT01
Experimental: Cohort 4 Bilateral high dose
9.9 x 10^10 (vg/mL) rAAV1-miHHT
 Genetic: Intraparenchymal rAAV1 - (mi)RNA HTT
Single dose MRI guided intraparenchymal infusion of rAAV1 - (mi)RNA HTT.
Other Name: VY-HTT01


Outcome Measures
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Primary Outcome Measures :
  1. Incidence and type of AEs [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    Safety will be assessed by measuring the number and type of AE or SAEs.


Secondary Outcome Measures :
  1. Level of VY-HTT01 in blood [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    Change in baseline of the levels of VY-HTT01 vector genome in blood over time.

  2. Unified Huntington Disease Rating Scale (UHDRS) [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    UHDRS will assess changes from baseline in summary scores of motor function, cognitive function, behavioral function, and functional abilities. UHDRS uses a 5-point ordinal scale ranging from 0-4 with the highest score indicating a more severe (worse) outcome.

  3. Clinical Global Impression (CGI) Measures [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    CGI-Global Improvement measure will assess changes from baseline in CGI-Severity of Illness score. Both CGI-Global Improvement and CGI- Severity measures are based on a 7-point scale, with the highest score indicating a more severe (worse) outcome.

  4. Huntington's Disease Quality of Life (HD-QOL) Measure [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    HD-QOL measure will assess changes from baseline in the HD-QOL score using a 40-question scale to identify quality of life in HD. HD-QOL is based on a 7-point scale of frequency ranging from "never" to "all of the time" with "extreme problems" indicating a more severe (worse) outcome.

  5. EuroQol 5 Dimension 5 Level (EQ-5D-5L) Measure [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    EQ-5D-5L measure will assess changes from baseline in the EQ-5D-5L score across 5 domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. The EQ-5D-5L is scored on a 5-level severity ranking that ranges from "no problems" through "extreme problems", with "extreme problems" indicating a more severe (worse) outcome.


Other Outcome Measures:
  1. Magnetic Resistance Imagining (MRI) [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    MRI assessments will include whole brain volume, white matter volume, gray matter volume, and ventricular volume, and volumes of the putamen and thalamus covered by VY-HTT01 infusions during surgery.

  2. Levels of HTT protein in CSF [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    Change from baseline in levels of HTT protein in CSF (Cerebrospinal fluid) over time.

  3. Levels of HTT protein in blood [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    Change from baseline in levels of HTT protein in blood over time.

  4. Huntington's Disease Cognitive Assessment Battery (HD-CAB) Measure [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    HD-CAB measure will assess changes from baseline in the HD-CAB score for cognitive dysfunction in early manifest HD patients. HD-CAB consists of 6 tests; (1) Symbol Digit Modality Test (SDMT), (2) Paced Tapping, (3) One Touch Stockings of Cambridge, (4) Emotional Recognition, (5) Trial Making B and (6) Hopkins Learning Test. A multi-component score is derived by transforming the subject's score on each cognitive test to a z-score. The six z-scores are averaged to produce the HD-CAB score. A positive change from baseline indicates improvement in cognitive function; a negative change indicates worsening in cognitive function.

  5. Level of Neurofilament Light chain (NfL) in CSF [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    Change from baseline in levels of NfL in CSF over time.

  6. Level of Neurofilament Light chain (NfL) in blood [ Time Frame: Collected for duration of study, average of 1 year after treatment ]
    Change from baseline in levels of NfL in blood over time.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Must be at least 18 years old.
  • Have CAGn repeat >39.
  • Have diagnostic confidence score of 4 based on motor, cognitive, or behavioral symptoms.
  • Have a TFC score of 13 to 11.
  • Have stable dosing of neurological and psychiatric medications.
  • Capable of giving informed consent.
  • Able to comply with all procedures and study visits.

Exclusion Criteria:

  • Have any significant structural or degenerative neurologic disease other than HD.
  • Have any chronic disability, significant systemic illness and/or, unstable medical condition, or clinical findings noted.
  • Have primary or secondary immune-compromise due to infections or medical conditions or chronic therapies.
  • Have contraindications to lumbar puncture or increased risks of bleeding upon surgery.
  • Started or changed dose of a concomitant CNS medication within 30 days.
  • Had prior neurosurgical procedures that could complicate the study procedures.
  • Have used any investigational therapies within 30 days prior to Screening, oligonucleotide therapies within 9 months prior to Baseline, or any prior gene therapy.
  • Male or female with reproductive capacity and is unwilling to use highly effective contraception for 12 months after surgery.
  • Have contraindications to MRI such as claustrophobia, embedded metal in the body, or known allergy or intolerance to contrast agents.
Contacts and Locations
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No Contacts or Locations Provided
More Information
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Responsible Party: Voyager Therapeutics
ClinicalTrials.gov Identifier: NCT04885114    
Other Study ID Numbers: VY-HTT01-1
First Posted: May 13, 2021    Key Record Dates
Last Update Posted: August 16, 2021
Last Verified: August 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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