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Safety and Proof-of-Concept (POC) Study With AMT-130 in Adults With Early Manifest Huntington 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.
 
ClinicalTrials.gov Identifier: NCT04120493
Recruitment Status : Recruiting
First Posted : October 9, 2019
Last Update Posted : January 13, 2020
Sponsor:
Information provided by (Responsible Party):
UniQure Biopharma B.V.

Tracking Information
First Submitted Date  ICMJE September 30, 2019
First Posted Date  ICMJE October 9, 2019
Last Update Posted Date January 13, 2020
Actual Study Start Date  ICMJE September 6, 2019
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 7, 2019)
Number and type of Adverse Events (AE) [ Time Frame: 18 months ]
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.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT04120493 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: October 7, 2019)
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)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: October 7, 2019)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Safety and Proof-of-Concept (POC) Study With AMT-130 in Adults With Early Manifest Huntington Disease
Official Title  ICMJE A Phase I/II, Randomized, Double-blind, Sham Control Study to Explore Safety, Tolerability, and Efficacy Signals of Multiple Ascending Doses of Striatally-Administered rAAV5-miHTT Total Huntingtin Gene (HTT) Lowering Therapy (AMT-130) in Early Manifest Huntington Disease
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, dose escalation, double-blind, imitation surgery, first-in-human (FIH) study.
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 improved Huntington disease signs in animal models.

This 5-year trial consists of a blinded 18-month Core Study Period to evaluate the safety and potential impact of AMT-130 on disease progression and an unblinded 3.5-year Long-Term Period with annual follow-up visits to evaluate the safety of AMT-130 and disease progression.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Huntington Disease
Intervention  ICMJE
  • Genetic: rAAV5-miHTT
    Single dose administration of rAAV5-miHTT gene therapy
    Other Name: AMT-130
  • Procedure: Imitation surgery
    Bilateral partial thickness burr holes placed, no intrastriatal injections
Study Arms  ICMJE
  • Experimental: Cohort 1
    Intrastriatal administration of low dose rAAV5-miHTT (6E12 gc/subject). Single dose administration.
    Intervention: Genetic: rAAV5-miHTT
  • Experimental: Cohort 2
    Intrastriatal administration of high dose rAAV5-miHTT (6E13 gc/subject). Single dose administration.
    Intervention: Genetic: rAAV5-miHTT
  • Sham Comparator: Imitation Surgery
    Imitation surgery patients randomized across both Cohort 1 and 2
    Intervention: Procedure: Imitation surgery
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 7, 2019)
26
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE May 2026
Estimated Primary Completion Date December 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • First 4 subjects in Cohort 1: early manifest HD (Stage 2). All remaining subjects in Cohort 1 and all subjects in Cohort 2: early manifest HD (Stages 1 and 2).
  • HTT gene expansion testing with the presence of ≥44 CAG repeats.
  • Striatal MRI volume requirements per hemisphere: Putamen ≥2.5 cm3 (per side); Caudate ≥2.0 cm3 (per side)
  • All HD concomitant medications stable for 3 months prior to Screening.

Exclusion Criteria:

  • 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, etc.) within 60 days prior to Screening or anytime over the duration of this study.
  • Presence of an implanted deep brain stimulation device.
  • 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.
  • Any contraindication to lumbar puncture or 3.0 Tesla MRI as per local guidelines.
  • Brain and spinal pathology that may interfere with CSF homeostasis and circulation, increased intracranial pressure (including presence of a shunt for the drainage of CSF or an implanted CNS catheter), malformations and/or tumors.
  • Hospitalization for any major medical or surgical procedure involving general anesthesia within 12 weeks of Screening or planned during the study.
  • Current use of medications that could improve or worsen chorea or other HD movements including typical neuroleptics, tetrabenazine and deutetrabenazine.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 25 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: David Cooper, MD, MBA 339-970-7081 amt130_clinical_trials@uniqure.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04120493
Other Study ID Numbers  ICMJE CT-AMT-130-01
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party UniQure Biopharma B.V.
Study Sponsor  ICMJE UniQure Biopharma B.V.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account UniQure Biopharma B.V.
Verification Date January 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP