Huntington's Disease Clinical Trial
Official 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
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).
Status | Recruiting |
Enrollment | 36 |
Est. completion date | June 2029 |
Est. primary completion date | April 2029 |
Accepts healthy volunteers | No |
Gender | All |
Age group | 25 Years to 65 Years |
Eligibility | Inclusion Criteria: 1. Able and willing to provide written informed consent prior to the study and study-related procedure 2. Subjects 25 to 65 years of age of both sexes 3a. Cohort 1 & 2: Early manifest HD as defined by a UHDRS total functional capacity (TFC) score of 9 to 13 and EITHER a diagnostic confidence level (DCL) of 4 OR a DCL of 3 if the subject either meets the definition of multidimensional manifest HD (UHDRS question 80) or has cognitive symptoms 3b. 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). 4. HTT gene expansion testing with the presence of =40 CAG repeats 5. Striatal MRI volume requirements per hemisphere: Putamen =2.5 cm3 (per side); Caudate =2.0 cm3 (per side) 6. 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 change in medication prior to anticipated administration procedure 7. Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol 8. All female subjects 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. Exclusion Criteria: 1. Evidence of suicide risk 2. Receipt of an experimental agent within 60 days or five half-lives prior to Screening or anytime over the duration of this study. 3. Participation in an investigational trial or investigational paradigm (such as exercise/physical activity, cognitive therapy, brain stimulation) within 60 days prior to Screening or anytime over the duration of this study. 4. Presence of an implanted deep brain stimulation device, ventriculoperitoneal or other CSF shunt, or other implanted catheter 5. Any history of gene therapy, RNA or DNA targeted HD specific investigational agents, such as antisense oligonucleotides (ASO), cell transplantation or any other experimental brain surgery. 6. Any contraindication to 3.0 Tesla MRI as per local guidelines 7. Brain and spinal pathology that may interfere with the surgical delivery of AMT-130 or represents a significant neurologic comorbid disorder 8. Any contraindication to lumbar puncture as per local guidelines 9. 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 10. Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study 11. 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 subject's safety or their ability to undergo the neurosurgical procedure or comply with the procedures and study visit schedule 12. Known or suspected intolerance or hypersensitivity to the investigational product(s), closely-related compounds, or any of the stated ingredients 13. 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 14. Known, documented infection with coronavirus disease 2019 (COVID-19) based upon any testing methodology: a. Within 8 weeks of anticipated Visit 2 (Baseline) for an asymptomatic patient or a patient who recovered from only mild, non-respiratory symptoms b. Within 12 weeks of anticipated Visit 2 (Baseline) for an asymptomatic patient (e.g. cough, dyspnea) who did not require hospitalization c. At any time for a symptomatic patient who is diabetic, immunocompromised, or hospitalized d. For any patient not already excluded by 14 a-c above: i. within 8 weeks of anticipated Visit 2 (Baseline) for any patient with residual respiratory or cardiac symptoms, such as fatigue, shortness of breath, and chest pain ii. Any patient with neurological symptoms associated with a symptomatic COVID-19 infection that might complicate assessment of HD progression |
Country | Name | City | State |
---|---|---|---|
United States | University of Michigan Department of Neurology | Ann Arbor | Michigan |
United States | Johns Hopkins University | Baltimore | Maryland |
United States | University of Alabama at Birmingham | Birmingham | Alabama |
United States | Beth Israel Deaconess Medical Center | Boston | Massachusetts |
United States | Rush University Medical Center | Chicago | Illinois |
United States | Ohio State University | Columbus | Ohio |
United States | CenExel Rocky Mountain Clinical Research | Englewood | Colorado |
United States | University of Florida College of Medicine | Gainesville | Florida |
United States | The University of Texas | Houston | Texas |
United States | Vanderbilt University Medical Center | Nashville | Tennessee |
United States | Virginia Commonwealth University VCU School of Medicine, Department of Neurology | Richmond | Virginia |
United States | University of California, San Francisco | San Francisco | California |
United States | University of Washington Medical Center | Seattle | Washington |
United States | University of Arizona | Tucson | Arizona |
Lead Sponsor | Collaborator |
---|---|
UniQure Biopharma B.V. |
United States,
Type | Measure | Description | Time frame | Safety issue |
---|---|---|---|---|
Other | CSF Mutant Protein (fM) | Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment. | Collected for duration of study through month 60 | |
Other | CSF/Serum Neurofilament Light Chain (pg/mL) | Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment. | Collected for duration of study through month 60 | |
Other | Unified Huntington Disease Rating Scale (UHDRS) | The UHDRS will assess changes from baseline in summary scores of domains of motor function, cognitive function, behavioral function, and functional abilities. | Collected for duration of study through month 60 | |
Other | Quantitative Motor (Q-Motor) Testing | Q-Motor testing will measure disease progression and responsiveness to AMT-130 treatment. | Collected for duration of study through month 60 | |
Other | Huntington's Disease Cognitive Assessment Battery (HD-CAB) | The HD-CAB measures cognitive dysfunction in late premanifest and early manifest HD patients. | Collected for duration of study through month 60 | |
Other | Magnetic Resonance Imaging (MRI) | MRI assessments will include whole brain volume, striatal region volumes, white matter volume, gray matter volume, ventricular volume, cortical thickness, and diffusion MRI measures. | Collected for duration of study through month 60 | |
Other | Magnetic Resonance Spectroscopy (MRS) | MRS will be collected using single-voxel point resolved spectroscopy of the left putamen and white matter region immediately adjacent to the left putamen. Neuronal health and gliosis will be evaluated by measuring total N-acetylaspartic acid (neuronal integrity marker) and myoinisitol (reactive astrocytosis marker) levels. | Collected for duration of study through month 60 | |
Other | Neuro-QoL Measures | The Neuro-QoL is a brief, reliable, valid, standardized set of patient reported, Health Related Quality of Life (HRQoL) measures for people living with neurological conditions. | Collected for duration of study through month 60 | |
Other | HDQLIFE Measures | The HDQLIFE is a measurement system that was designed to provide a brief, reliable and valid assessment of HRQoL in HD and consists of NeuroQoL measures that have been validated in the HD population and several new HD specific measures. | Collected for duration of study through month 60 | |
Other | Hospital Anxiety and Depression Scale (HADS) | The HADS is a 14-item, self-report measure that has been shown to be reliable and valid for identifying depression and anxiety in adults who are physically ill. Each item is scored from 0 (no anxiety or depression) to 3 (abnormal anxiety or depression) for a maximum total score of 21. | Collected for duration of study through month 60 | |
Primary | Number and type of Adverse Events (AE) | Safety will be assessed by adverse events (AEs) related to clinical safety laboratory tests, vital signs, electrocardiograms (ECGs), neurological and physical examinations, rAAV5 vector shedding, immunogenicity response, suicidality risk [Columbia-Suicide Severity Rating Scale [C-SSRS)], changes in global cognitive functioning [Montreal Cognitive Assessment Scale (MoCA)] and MRI measures of edema, inflammation, volume loss and structural changes. | 12 months (Cohorts 1 & 2) and 12 months (Cohort 3) | |
Secondary | Duration of persistence of AMT-130 in the brain | Change over time in levels of AMT-130-derived Vector DNA and miRNA Expression in the Cerebrospinal Fluid (CSF) | Collected for duration of study through month 60 |
Status | Clinical Trial | Phase | |
---|---|---|---|
Completed |
NCT02956148 -
Follow-up Measurement of Brain PDE10A Enzyme Levels in Huntington´s Disease Gene Expansion Carriers
|
Early Phase 1 | |
Terminated |
NCT02494778 -
A Study Evaluating if Pridopidine is Safe, Efficacious, and Tolerable in Patients With Huntington's Disease
|
Phase 2 | |
Completed |
NCT02197130 -
Randomized, Placebo Controlled Study Of The Efficacy And Safety Of PF-02545920 In Subjects With Huntington's Disease
|
Phase 2 | |
Completed |
NCT02216474 -
Brain Stimulation in Movement Disorders
|
N/A | |
Completed |
NCT02208934 -
Study To Assess the Safety and Tolerability of Single Ascending Oral Doses of PBF-999 in Healthy Young Male Volunteers
|
Phase 1 | |
Completed |
NCT01806896 -
Study Evaluating The Safety, Tolerability And Brain Function Of 2 Doses Of PF-0254920 In Subjects With Early Huntington's Disease
|
Phase 2 | |
Completed |
NCT01502046 -
Neuroprotection by Cannabinoids in Huntington's Disease
|
Phase 2 | |
Terminated |
NCT00712426 -
Creatine Safety, Tolerability, & Efficacy in Huntington's Disease (CREST-E)
|
Phase 3 | |
Completed |
NCT00670709 -
Examination of Quantitative Electroencephalographic (QEEG) Biomarkers in Huntington's Disease
|
||
Completed |
NCT00029874 -
Minocycline in Patients With Huntington's Disease
|
Phase 1/Phase 2 | |
Terminated |
NCT02231580 -
Study Exploring Safety, Pharmacokinetic and Pharmacodynamic of BN82451 in Male Huntington's Disease Patients
|
Phase 2 | |
Completed |
NCT02215616 -
A Clinical Study in Participants With Huntington's Disease (HD) to Assess Efficacy and Safety of Three Oral Doses of Laquinimod
|
Phase 2 | |
Not yet recruiting |
NCT02551705 -
Functional Imaging of Social Cognition in Premanifest Huntington's Disease
|
N/A | |
Active, not recruiting |
NCT02101957 -
Multicentric Trial of the Treatment of Huntington's Disease by Cysteamine (RP103)
|
Phase 2/Phase 3 | |
Completed |
NCT00990613 -
A Study Evaluating The Absorption Of Dimebon Into The Body From A Dimebon Solution Applied To The Skin
|
Phase 1 | |
Completed |
NCT00975481 -
A Study To Evaluate The Abuse Potential Of Single Oral Doses Of Dimebon (Latrepirdine) In Healthy Recreational Polydrug Users
|
Phase 1 | |
Completed |
NCT01521832 -
Escalating Dose Study in Healthy Volunteers With SEN0014196
|
Phase 1 | |
Completed |
NCT00387270 -
Safety Study of the Novel Drug Dimebon to Treat Patients With Huntington's Disease
|
Phase 1/Phase 2 | |
Completed |
NCT00095355 -
Effects of Lithium and Divalproex`on Brain-Derived Neurotrophic Factor in Huntington's Disease
|
Phase 2 | |
Completed |
NCT00026988 -
Creatine Therapy for Huntington's Disease
|
Phase 1/Phase 2 |