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Safety and Proof-of-Concept (POC) Study With AMT-130 in Adults With Early Manifest Huntington's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT04120493
Recruitment Status : Recruiting
First Posted : October 9, 2019
Last Update Posted : October 18, 2023
Information provided by (Responsible Party):
UniQure Biopharma B.V.

Brief Summary:

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).

Condition or disease Intervention/treatment Phase
Huntington's Disease Genetic: intra-striatal rAAV5-miHTT Other: Imitation (sham) surgery Phase 1 Phase 2

Detailed Description:

AMT-130 is an investigational, single administration gene therapy intended to modify the disease course for HD. Preclinical studies have shown that AMT-130 lowers huntingtin protein and is associated with decreased progression of Huntington's Disease signs in animal models.

Cohort 1 & 2 consists of a blinded 12-month Core Study Period to evaluate the safety and potential impact of AMT-130 on disease progression and an unblinded 4-year Long-Term Period with periodic follow-up visits to evaluate the safety of AMT-130 and disease progression in treated individuals. Cohort 2 Sham participants who do not cross over to receive AMT-130 treatment will have the opportunity to participate in the Optional Extended Follow-Up Period and will be followed for an additional 2 years.

Following completion of the 12-month blinded post treatment follow-up period (Cohorts 1 & 2 only), once the crossover has been activated after review of data by the DSMB, subjects randomized to the imitation (sham) procedure who continue to meet inclusion/exclusion criteria will be allowed to crossover to receive AMT-130 treatment.

Cohort 3 participants will receive AMT-130 either high or low dose. Following completion of the Month 12 visit, they will be unblinded to their treatment arm. Cohort 3 will further evaluate the safety and exploratory efficacy data of low or high dose AMT-130 together with peri- and post-operative glucocorticoids.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 36 participants
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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
Actual Study Start Date : September 6, 2019
Estimated Primary Completion Date : April 2029
Estimated Study Completion Date : June 2029

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Cohort 1
Low dose rAAV5-miHTT (6x10^12 gc/subject).
Genetic: intra-striatal rAAV5-miHTT
One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain
Other Name: AMT-130

Experimental: Cohort 2
High dose rAAV5-miHTT (6x10^13 gc/subject).
Genetic: intra-striatal rAAV5-miHTT
One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain
Other Name: AMT-130

Sham Comparator: Cohorts 1, 2
Imitation (sham) surgery
Other: Imitation (sham) surgery
Simulated surgical procedure with skin incisions only; no intrastriatal injections and no burr holes through the skull

Experimental: Cohort 3

Low dose rAAV5-miHTT (6x10^12 gc/subject).

High dose rAAV5-miHTT (6x10^13 gc/subject).

Genetic: intra-striatal rAAV5-miHTT
One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain
Other Name: AMT-130

Primary Outcome Measures :
  1. Number and type of Adverse Events (AE) [ Time Frame: 12 months (Cohorts 1 & 2) and 12 months (Cohort 3) ]
    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.

Secondary Outcome Measures :
  1. Duration of persistence of AMT-130 in the brain [ Time Frame: Collected for duration of study through month 60 ]
    Change over time in levels of AMT-130-derived Vector DNA and miRNA Expression in the Cerebrospinal Fluid (CSF)

Other Outcome Measures:
  1. CSF Mutant Protein (fM) [ Time Frame: Collected for duration of study through month 60 ]
    Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment.

  2. CSF/Serum Neurofilament Light Chain (pg/mL) [ Time Frame: Collected for duration of study through month 60 ]
    Will be used as an exploratory biomarker to measure disease progression and responsiveness to AMT-130 treatment.

  3. Unified Huntington Disease Rating Scale (UHDRS) [ Time Frame: Collected for duration of study through month 60 ]
    The UHDRS will assess changes from baseline in summary scores of domains of motor function, cognitive function, behavioral function, and functional abilities.

  4. Quantitative Motor (Q-Motor) Testing [ Time Frame: Collected for duration of study through month 60 ]
    Q-Motor testing will measure disease progression and responsiveness to AMT-130 treatment.

  5. Huntington's Disease Cognitive Assessment Battery (HD-CAB) [ Time Frame: Collected for duration of study through month 60 ]
    The HD-CAB measures cognitive dysfunction in late premanifest and early manifest HD patients.

  6. Magnetic Resonance Imaging (MRI) [ Time Frame: Collected for duration of study through month 60 ]
    MRI assessments will include whole brain volume, striatal region volumes, white matter volume, gray matter volume, ventricular volume, cortical thickness, and diffusion MRI measures.

  7. Magnetic Resonance Spectroscopy (MRS) [ Time Frame: Collected for duration of study through month 60 ]
    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.

  8. Neuro-QoL Measures [ Time Frame: Collected for duration of study through month 60 ]
    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.

  9. HDQLIFE Measures [ Time Frame: Collected for duration of study through month 60 ]
    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.

  10. Hospital Anxiety and Depression Scale (HADS) [ Time Frame: Collected for duration of study through month 60 ]
    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.

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:   25 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

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 identifier (NCT number): NCT04120493

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Contact: Diane Lopez, MS 781-777-3697
Contact: Elizabeth Eyler

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United States, Alabama
University of Alabama at Birmingham Recruiting
Birmingham, Alabama, United States, 35294-0111
Contact: Jenna Smith    205-996-2807   
Principal Investigator: Victor Sung, MD         
United States, Arizona
University of Arizona Not yet recruiting
Tucson, Arizona, United States, 85724
Contact: Paul Larson, MD         
United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94158
Contact: Zach Lamson    415-502-0670   
Principal Investigator: Michael Geschwind, MD, Ph.D.         
United States, Colorado
CenExel Rocky Mountain Clinical Research Recruiting
Englewood, Colorado, United States, 80113
Contact: Jessica Crall    303-357-5456   
Principal Investigator: Rajeev Kumar, MD         
United States, Florida
University of Florida College of Medicine Withdrawn
Gainesville, Florida, United States, 32610
United States, Illinois
Rush University Medical Center Recruiting
Chicago, Illinois, United States, 60612
Contact: Tyler Svymbersky    312-563-0676   
Principal Investigator: Deborah Hall, MD, Ph.D         
United States, Maryland
Johns Hopkins University Recruiting
Baltimore, Maryland, United States, 21287
Contact: Kia Ultz    410-955-1349   
Contact: Mollie Webb Jenckes   
Principal Investigator: Christopher Ross, MD, Ph.D         
United States, Massachusetts
Beth Israel Deaconess Medical Center Withdrawn
Boston, Massachusetts, United States, 02215
United States, Michigan
University of Michigan Department of Neurology Recruiting
Ann Arbor, Michigan, United States, 48105
Contact: Angela Stovall    734-647-4787   
Principal Investigator: Praveen Dayalu, MD         
United States, Ohio
Ohio State University Recruiting
Columbus, Ohio, United States, 43210
Contact: Nicole Vrettos   
Principal Investigator: Sandra Kostyk, M.D., Ph.D.         
United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Danielle Buchanan    615-875-3274   
Principal Investigator: Daniel Claassen, MD         
United States, Texas
The University of Texas Recruiting
Houston, Texas, United States, 77030
Contact: Jamie Sims    713-500-7763   
Principal Investigator: Erin Furr-Stimming, MD         
United States, Virginia
Virginia Commonwealth University VCU School of Medicine, Department of Neurology Recruiting
Richmond, Virginia, United States, 23298
Contact: Kara L McHaney    804-382-0076   
Principal Investigator: Matthew Barrett, MD         
United States, Washington
University of Washington Medical Center Recruiting
Seattle, Washington, United States, 98195
Contact: Debra Del Castillo    206-543-3647   
Principal Investigator: Ali Samii, MD         
Sponsors and Collaborators
UniQure Biopharma B.V.
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Principal Investigator: Kenechi Ejebe, MD UniQure Biopharma B.V.
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: UniQure Biopharma B.V. Identifier: NCT04120493    
Other Study ID Numbers: CT-AMT-130-01
First Posted: October 9, 2019    Key Record Dates
Last Update Posted: October 18, 2023
Last Verified: October 2023

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by UniQure Biopharma B.V.:
Gene therapy
AAV (adeno-associated virus)
serotype 5 AAV (adeno-associated virus)
serotype 5
Viral vector
Huntington's Disease (HD)
Additional relevant MeSH terms:
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Huntington Disease
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Cognition Disorders
Neurocognitive Disorders
Mental Disorders