Safety and Proof-of-Concept (POC) Study With AMT-130 in Adults With Early Manifest Huntington's Disease
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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. |
| ClinicalTrials.gov Identifier: NCT04120493 |
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Recruitment Status :
Recruiting
First Posted : October 9, 2019
Last Update Posted : May 1, 2024
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Huntington's Disease | Genetic: intra-striatal rAAV5-miHTT Other: Imitation (sham) surgery | Phase 1 Phase 2 |
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 either high or low dose AMT-130. Following completion of the Month 36 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. Cohort 3 participants will also receive pre and post-operative immunosuppressant therapies composed of dexamethasone, sirolimus, and rituximab.
| 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 |
| Arm | Intervention/treatment |
|---|---|
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Experimental: Cohort 1
Low dose rAAV5-miHTT (6x10^12 gc/subject).
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Genetic: intra-striatal rAAV5-miHTT
One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain
Other Name: AMT-130 |
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Experimental: Cohort 2
High dose rAAV5-miHTT (6x10^13 gc/subject).
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Genetic: intra-striatal rAAV5-miHTT
One time MRI-guided stereotaxic infusion of rAAV5-miHTT into the brain
Other Name: AMT-130 |
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Sham Comparator: Cohorts 1, 2
Imitation (sham) surgery
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Other: Imitation (sham) surgery
Simulated surgical procedure with skin incisions only; no intrastriatal injections and no burr holes through the skull |
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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 |
- 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.
- 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 Expression in the Cerebrospinal Fluid (CSF)
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
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.
| Ages Eligible for Study: | 25 Years to 65 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- 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
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 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.
Exclusion Criteria:
- 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 anytime 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.
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): NCT04120493
| Contact: Diane Lopez, MS | 781-777-3697 | amt130_clinical_trials@uniqure.com | |
| Contact: Elizabeth Eyler | amt130_clinical_trials@uniqure.com |
| United States, Alabama | |
| University of Alabama at Birmingham | Recruiting |
| Birmingham, Alabama, United States, 35294-0111 | |
| Contact: Jenna Smith 205-996-2807 jltidwell@uabmc.edu | |
| Principal Investigator: Victor Sung, MD | |
| United States, Arizona | |
| University of Arizona (Surgical Site Only) | 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 zach.lamson@ucsf.edu | |
| 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 j.crall@cenexel.com | |
| 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 Tyler_Svymbersky@rush.edu | |
| 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 kcarte23@jhmi.edu | |
| Contact: Mollie Webb Jenckes mjenckes@jhmi.edu | |
| Principal Investigator: Jee Bang, MD, M.P.H. | |
| 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 astovall@med.umich.edu | |
| Principal Investigator: Praveen Dayalu, MD | |
| United States, Ohio | |
| Ohio State University | Recruiting |
| Columbus, Ohio, United States, 43210 | |
| Contact: Nicole Vrettos Nicole.Vrettos@osumc.edu | |
| 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 danielle.a.buchanan@vumc.org | |
| Principal Investigator: Daniel Claassen, MD | |
| United States, Texas | |
| The University of Texas | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Jamie Sims 713-500-7763 Jamie.Sims@uth.tmc.edu | |
| 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 kara.mchaney@vcuhealth.org | |
| 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 debradel@uw.edu | |
| Principal Investigator: Ali Samii, MD | |
| Study Director: | David Margolin, MD, PhD | UniQure Biopharma B.V. |
| Responsible Party: | UniQure Biopharma B.V. |
| ClinicalTrials.gov Identifier: | NCT04120493 |
| Other Study ID Numbers: |
CT-AMT-130-01 |
| First Posted: | October 9, 2019 Key Record Dates |
| Last Update Posted: | May 1, 2024 |
| Last Verified: | April 2024 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Gene therapy AAV (adeno-associated virus) serotype 5 AAV (adeno-associated virus) serotype 5 |
Viral vector miHTT muHTT Huntington's Disease (HD) |
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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 |