- Study Director: Michael Geschwind, MD, PhD
- Sponsor: UniQure Biopharma BV
- Recruiting? Active trial, closed to new enrollment
- Official Study Title: A Phase I/II, Randomized, Double-Blind, Sham Control Study to Explore Safety, Tolerability, and Efficacy Signals of Multiple Doses of Striatally-Administered RAAV5-miHTT Total Huntingtin Gene (HTT) Lowering Therapy (AMT-130) in Early Manifest Huntington's Disease
- ClinicalTrials.gov Identifier: NCT04120493
- Conditions Studied: Huntington's disease
- Intervention: AMT-130, an investigational, single-administration gene therapy intended to modify the disease course for HD.
- Phase: Phase 1/2
- Duration of Participation: Approximately 5 years
Purpose of the Study
This is the first study of AMT-130 in patients with early manifest HD and is designed to establish safety and proof-of-concept (PoC). CT-AMT-130-01 is a Phase I/II, randomized, multicenter, multiple-dose, double-blind, imitation surgery, first-in-human (FIH) study. Cohort 3 participants will receive either high or low dose (1:1 randomization). Participants enrolled in Cohort 3 will also receive an immunosuppression regimen consisting of dexamethasone, sirolimus, and rituximab.
Eligibility
- Able and willing to provide written informed consent prior to the study and study-related procedure
- Participants 25 to 65 years of age of both sexes
- Cohort 3: Early manifest HD as defined by a UHDRS TFC score of ≥11 and either a DCL of 4 or a DCL of 3 with either a positive "Yes" response to UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 criteria for cognitive disorder (Movement Disorder Society Task Force criteria).
- HTT gene expansion testing with the presence of ≥40 CAG repeats
- Striatal MRI volume requirements per hemisphere: Putamen ≥2.5 cm3 (per side); Caudate ≥2.0 cm3 (per side)
- All HD concomitant medications (addressing motor, behavioral, and cognitive symptoms) must be stable for 3 months prior to Screening with no change in clinical symptoms requiring a change in medication prior to the anticipated administration procedure
- Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol
- All female participants of childbearing potential (FOCP) must have a negative serum pregnancy test at Screening, (and Visit 1A, as appropriate), a negative pregnancy urine dipstick at Baseline, and not be breastfeeding. All FOCPs and sexually mature males must be compliant with a highly effective birth control method.
- Evidence of suicide risk
- Receipt of an experimental agent within 60 days or five half-lives prior to Screening or anytime over the duration of this study.
- Participation in an investigational trial or investigational paradigm (such as exercise/physical activity, cognitive therapy, brain stimulation) within 60 days prior to Screening or any time over the duration of this study.
- Presence of an implanted deep brain stimulation device, ventriculoperitoneal or other CSF shunt, or other implanted catheter
- Any history of gene therapy, RNA- or DNA-targeted HD-specific investigational agents, such as antisense oligonucleotides (ASOs), cell transplantation, or any other experimental brain surgery.
- Any contraindication to 3.0 Tesla MRI as per local guidelines
- Brain and spinal pathology that may interfere with the surgical delivery of AMT-130 or represents a significant neurologic comorbid disorder
- Any contraindication to lumbar puncture as per local guidelines
- Malignancy within 5 years of Screening, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated
- Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study
- Current or recurrent disease, (including pre-existing cardiovascular or pulmonary conditions) infection, or other significant concurrent medical condition or medications that could confound clinical and laboratory evaluations or could affect a participant's safety or their ability to undergo the neurosurgical procedure or comply with the procedures and study visit schedule
- Known or suspected intolerance or hypersensitivity to the investigational product(s), closely related compounds, or any of the stated ingredients
- Any known allergy to gadoteridol (ProHance)
- Screening laboratory values (as measured by the central laboratory): a. Alanine aminotransferase (ALT) >2 × upper limit of normal (ULN) b. Aspartate aminotransferase (AST) >2 × ULN c. Total bilirubin >2 × ULN d. Alkaline phosphatase (ALP) >2 × ULN e. Creatinine >1.5 × ULN f. Platelet count <100,000/mm3g.Prothrombin time (PT) >1.2 × ULN h. Partial thromboplastin time (PTT) >1.2 × ULN
- Known immunocompromised status including participants who have undergone organ transplantation; or who test positive at Screening for human immunodeficiency virus (HIV); or who are at risk of pathogen reactivation if immunosuppressed, including participants who test positive at Screening for hepatitis C virus antibody (anti-HCV), hepatitis C virus ribonucleic acid (HCV RNA), or hepatitis B surface antigen (HBsAg); or who have history of active tuberculosis or a positive tuberculosis blood test during Screening. For participants with an indeterminate tuberculosis blood test result or positive tuberculosis test result, repeat testing is recommended.
- Known allergy, sensitivity, or other contraindication to medications in the immunosuppression regimen in this protocol.
- Any participant with an active infection (e.g., coronavirus disease 2019 [COVID-19]) at Screening or at the time of treatment that requires medical intervention. Participants may rescreen, or if screened eligible and an open surgical slot is available, may receive treatment after recovery.
What to Expect
Testing
- A screening visit to confirm eligibility. Approved subjects will complete a baseline visit and then begin the investigational period.
- Safety, tolerability, and efficacy assessments will be performed at all visits.
- Functional tests and questionnaires relating to symptoms will be performed at all visits.
- On-site blood draws will be performed at all visits.
- MR Imaging will be performed.
- AMT-130 participants cannot participate in other clinical trials of investigational compounds. Participants may still be eligible for AMT-130 if they are taking other prescribed medications.
The Frequency of Visits
Monthly
Materials Needed Before Evaluation
Medical history and confirmed genetic diagnosis, or suspected diagnosis based on family history
Costs
No costs will be charged for any of the study procedures. Parking will be validated at UCSF public garages for all study visits.
Contact Information
If you are interested in participating in this trial or have any questions, please contact the study coordinators: Zach Lamson at [email protected] or Hannah Robins at [email protected].
Find additional information at the UCSF Clinical Trials website.
