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Trial record 1 of 2 for:    AMT-130
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Safety and Efficacy of AMT-130 in European Adults With Early Manifest Huntington's Disease

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ClinicalTrials.gov Identifier: NCT05243017
Recruitment Status : Recruiting
First Posted : February 16, 2022
Last Update Posted : May 6, 2024
Sponsor:
Information provided by (Responsible Party):
UniQure Biopharma B.V.

Study Description
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Brief Summary:

This is the second study of AMT-130 in patients with early manifest HD and is designed as part of an integrated two-study phase I/II program under a single data safety monitoring board (DSMB) with staggered enrollment based upon continued demonstration of safety of AMT-130 administration.

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 Disease Genetic: intra-striatal rAAV5-miHTT Phase 1 Phase 2

Detailed Description:

The aim of the European study is to build upon the safety demonstrated in the first human dose (FHD) randomized, double blind, sham-controlled sequential dose escalation study (CT-AMT-130-01; clinicaltrials.gov NCT04120493) being conducted in the US and expand the number of patients exposed to the two doses to provide sufficient sample size for comparisons of safety and efficacy. CT-AMT-130-02 is a Phase Ib/II open-label (Cohorts 1 & 2), randomized (Cohort 3 only) sequential multiple dose study that will be conducted in approximately 5 to 8 European HD centers; 2 of these centers will serve as surgical sites. Both studies will share a common set of clinical, safety, imaging, and biomarker evaluations over 5 years of follow-up. The DSMB will evaluate safety and other parameters to enable the staggered treatment of patients within each of the dosing cohorts

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 Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: The first cohort will be treated with low dose, and a total of 6 enrolled participants is anticipated. The second cohort will be treated with high dose, and a total of 9 enrolled participants is anticipated.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase Ib/II Randomized, Double-Blind 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 : October 7, 2021
Estimated Primary Completion Date : March 2029
Estimated Study Completion Date : October 7, 2029

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1
Low dose AMT-130 (6 × 10^12 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 AMT-130 (6 × 10^13 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 3

Low dose AMT-130 (6 × 10^12 gc/subject)

High dose AMT-130 (6 × 10^13 gc/subject)

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


Outcome Measures
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Primary Outcome Measures :
  1. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Adverse Events [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Type and incidence of Adverse Events (AEs)


  2. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Vital Signs - Blood Pressure [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in blood pressure (mmHg)


  3. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Vital Signs - Respiratory Rate [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in respiratory rate (BPM)


  4. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Vital Signs - Heart Rate [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in heart rate (BPM)


  5. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by Electrocardiograms [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in electrocardiograms (ECGs) for any clinically significant abnormalities or clinically significant worsening. (normal or abnormal)


  6. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by changes documented in the neurological examinations [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in neurological examinations including mental status, cranial nerves, sensory, motor, fine motor, reflexes, and gait (normal or abnormal)


  7. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by changes documented in the physical examinations [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in physical examinations assessed by physical appearance, HEENT, Neck, Chest and Lungs, Cardiovascular, Abdomen, Musculoskeletal, and Genitourinary (normal or abnormal)


  8. Evaluate the safety and tolerability by number of participants with clinically significant changes in laboratory tests - Clinical Chemistry [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in Clinical Chemistry laboratory tests with clinical significance.


  9. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by number of participants with clinically significant laboratory tests - hematology [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Changes from baseline in hematology laboratory tests with clinical significance.


  10. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by number of participants with clinical significant laboratory tests - urinalysis [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change from baseline in routine urinalysis test with clinical significance.


  11. Evaluate the safety and tolerability o by number of participants with clinical significant changes in cerebrospinal fluid (CSF) analysis [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change from baseline in CSF analysis with clinical significance.


  12. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by vector shedding [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in AAV5 vector shedding


  13. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in microglial activation (YKL-40) (pg/mL)


  14. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in antibodies against AAV5 (g/L)


  15. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in cytokines (pg/mL)


  16. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in ELISpot


  17. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by laboratory testing serum and CSF for biomarkers [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change over time in astroglial activation (GFAP) (pg/mL)


  18. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by cognitive assessment [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change from baseline to Day 14 and Month 1 in the Montreal Cognitive Assessment (MoCA)


  19. Evaluate the safety and tolerability of bilateral striatal delivery of AMT-130 as a total HTT gene lowering therapy in adult subjects with early manifest HD assessed by number of participants with changes in MRI [ Time Frame: 6 months ]

    Evaluation will be assessed by;

    - Change from baseline will be measured by edema, inflammation, volume loss, and structural changes as measured by the following MRI pulse sequences, T1, T2 and diffusion MRI (dMRI)



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 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. Mean changes from baseline in summary scores for the 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 to capture the current disease status.

  4. Changes over time in 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. Changes over time in Neurological Disorders Quality of Life in Neurological Disorder Measures (Neuro-QoL) [ 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.

  6. Magnetic Resonance Imaging (MRI) - Brain Volumes [ 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(cm^3)

  7. Magnetic Resonance Imaging (MRI) - Cortical Thickness [ Time Frame: Collected for duration of study through month 60 ]
    MRI assessments will include cortical thickness (mm)

  8. Diffusion Magnetic Resonance Imaging (MRI) [ Time Frame: Collected for duration of study through month 60 ]
    MRI assessments will include diffusion MRI measures mm2/s


Eligibility Criteria
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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
Criteria

Inclusion Criteria:

  1. Able and willing to provide written informed consent prior to the study and study-related procedure.
  2. Male and female participants 25-65 years of age.

  3. Cohorts 1 & 2:

    1. a DCL of 4 OR
    2. a DCL of 3 with either a positive ("Yes") response to the UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 criteria for cognitive disorder (American Psychiatric Association, 2013; MDS Task Force criteria).

  4. Cohort 3:

    1. a DCL of 4 OR
    2. a DCL of 3 with either a positive ("Yes") response to the UHDRS Question 80 (multidimensional manifest diagnosis on motor, cognitive, behavioral, functional) or DSM5 criteria for cognitive disorder (American Psychiatric Association, 2013; MDS Task Force criteria).
  5. HTT gene expansion testing with the presence of ≥40 CAG repeats (confirmed by genetic testing at central laboratory).

  6. Striatal MRI volume requirements per hemisphere:

    1. Putamen ≥2.5 cm3 (per side)
    2. Caudate ≥2.0 cm3 (per side)
  7. 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.
  8. Able and willing to comply with all procedures and the study visit schedule as outlined in the protocol.
  9. All female participants of childbearing potential (FCOP) must have 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 highly effective birth control method as outlined in Section 4.5.

Exclusion Criteria:

  1. Evidence of suicide risk, defined as:

    1. Suicide attempt within 1 year prior to Screening (Visit 1/1A)
    2. Suicidal ideation as defined by a positive response to question 5 on Columbia-Suicide Severity Rating Scale (C-SSRS) Suicidal Ideation Section within 60 days prior to Screening (Visit 1/1A)
    3. Significant risk of suicide as judged by the Investigator
  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, etc.) 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 (ASOs), cell transplantation or any other experimental brain surgery.
  6. Any contraindication to lumbar puncture or 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 3.0 Tesla MRI 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 participant's safety or their ability to undergo a neurosurgical procedure (10+ hour surgical 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. Any known allergy to gadoteridol (ProHance).

  14. Screening laboratory values (as measured by the central laboratory):

    1. Alanine aminotransferase (ALT) >2 × upper limit of normal (ULN)
    2. Aspartate aminotransferase (AST) >2 × ULN
    3. Total bilirubin >2 × ULN
    4. Alkaline phosphatase (ALP) >2 × ULN
    5. Creatinine >1.5 × ULN
    6. Platelet count <100,000/mm3
    7. Prothrombin time (PT) >1.2 × ULN
    8. Partial thromboplastin time (PTT) >1.2 × ULN
  15. 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) 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.
  16. Known allergy, sensitivity, or other contraindication to immunosuppression regimens in this protocol.
  17. . 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.
Contacts and Locations
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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 ClinicalTrials.gov identifier (NCT number): NCT05243017


Contacts
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Contact: Diane Lopez, MS 781-777-3697 amt130_clinical_trials@uniqure.com
Contact: Elizabeth Eyler 781-491-6683 amt130_clinical_trials@uniqure.com

Locations
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Germany
Universitaetsklinikum Düsseldorf Withdrawn
Düsseldorf, Germany
George Huntington Institute Withdrawn
Münster, Germany
Poland
Instytut Psychiatrii i Neurologii Recruiting
Warsaw, Poland
Contact: Magdalena Skutnik    +48 503 196 807    mskutnik@ipin.edu.pl   
Principal Investigator: Grzegorz Witkowski         
Interventional Neuro Center Active, not recruiting
Warsaw, Poland
United Kingdom
Cardiff University Recruiting
Cardiff, United Kingdom
Contact: Hel Hughes    +44 2920 745302    Helen.Hughes10@wales.nhs.uk   
Principal Investigator: William Gray         
National Hospital for Neurology & Neurosurgery Recruiting
London, United Kingdom
Contact: Miguel Alvarez       miguel.alvarez.13@ucl.ac.uk   
Principal Investigator: Edward Wild         
Sponsors and Collaborators
UniQure Biopharma B.V.
Investigators
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Study Director: David Margolin, MD, PhD UniQure Biopharma B.V.
More Information
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Responsible Party: UniQure Biopharma B.V.
ClinicalTrials.gov Identifier: NCT05243017    
Other Study ID Numbers: CT-AMT-130-02
First Posted: February 16, 2022    Key Record Dates
Last Update Posted: May 6, 2024
Last Verified: May 2024

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Studies a U.S. FDA-regulated Drug Product: No
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
miHTT
muHTT
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
Dementia
Chorea
Dyskinesias
 Movement Disorders
Heredodegenerative Disorders, Nervous System
Neurodegenerative Diseases
Genetic Diseases, Inborn
Cognition Disorders
Neurocognitive Disorders
Mental Disorders