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A Dose-escalation and Safety & Efficacy Study of AXO-AAV-GM2 in Tay-Sachs or Sandhoff Disease

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ClinicalTrials.gov Identifier: NCT04669535
Recruitment Status : Recruiting
First Posted : December 17, 2020
Last Update Posted : January 29, 2021
Sponsor:
Collaborators:
University of Massachusetts, Worcester
Massachusetts General Hospital
Information provided by (Responsible Party):
Sio Gene Therapies

Tracking Information
First Submitted Date  ICMJE November 23, 2020
First Posted Date  ICMJE December 17, 2020
Last Update Posted Date January 29, 2021
Actual Study Start Date  ICMJE January 15, 2021
Estimated Primary Completion Date November 2024   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 8, 2020)
Incidence, severity, seriousness and relatedness to treatment of treatment emergent adverse events [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 8, 2020)
  • Number of participants with abnormal vital signs [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]
  • Number of participants with abnormal physical exam per investigator assessment [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]
  • Number of participants with abnormal clinical safety laboratory tests on blood/urine/CSF [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]
  • Electroencephalograms alpha, beta, delta, and theta wave frequencies (Hz) [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]
  • Serum cellular and antibody immune response to vector capsid/transgene [ Time Frame: 48 weeks (infantile-onset participants) to 96 weeks (juvenile-onset participants) ]
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Dose-escalation and Safety & Efficacy Study of AXO-AAV-GM2 in Tay-Sachs or Sandhoff Disease
Official Title  ICMJE A Two-Stage, Dose-Escalation and Safety & Efficacy Study of Bilateral Intraparenchymal Thalamic and Intracisternal/Intrathecal Administration of AXO-AAV-GM2 in Tay-Sachs or Sandhoff Disease
Brief Summary

The AXO-GM2-001 study is an open-label, two-stage clinical trial designed to evaluate safety and dose-escalation (Stage 1) and safety and efficacy (Stage 2) of a bilateral thalamic and intracisternal/intrathecal infusion of AXO-AAV-GM2 in pediatric participants with GM2 Gangliosidosis (also known as Tay-Sachs or Sandhoff Diseases), a set of rare and fatal pediatric neurodegenerative genetic disorders caused by defects in the HEXA (leading to Tay-Sachs disease) or HEXB (leading to Sandhoff disease) genes that encode the two subunits of the β-hexosaminidase A (HexA) enzyme. AXO-AAV-GM2 is an investigational gene therapy that aims to restore HexA function by introducing a functional copy of the HEXA and HEXB genes via co-administration of two vectors utilizing the neurotropic adeno-associated virus recombinant human 8 serotype (AAVrh.8) capsid carrying the human HEXA or HEXB cDNA.

The trial is expected to enroll pediatric participants with Tay-Sachs or Sandhoff Diseases, where infantile-onset participants will range from 6 months to 20 months old, and juvenile-onset participants will range from 2 years to 12 years old.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Tay-Sachs Disease
  • Sandhoff Disease
Intervention  ICMJE
  • Biological: AXO-AAV-GM2 Starting Dose
    1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).
    Other Name: AAVrh8-HEXA and AAVrh8-HEXB
  • Biological: AXO-AAV-GM2 Low Dose
    1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).
    Other Name: AAVrh8-HEXA and AAVrh8-HEXB
  • Biological: AXO-AAV-GM2 Middle Dose
    1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).
    Other Name: AAVrh8-HEXA and AAVrh8-HEXB
  • Biological: AXO-AAV-GM2 High Dose
    1:1 ratio of AAVrh8-HEXA and AAVrh8-HEXB, administered via bilateral thalamic (BiTh) and dual intracisterna magna (ICM)/intrathecal (IT) administration into the cerebrospinal fluid (CSF).
    Other Name: AAVrh8-HEXA and AAVrh8-HEXB
Study Arms  ICMJE Experimental: AXO-AAV-GM2
AXO-AAV-GM2 infusion
Interventions:
  • Biological: AXO-AAV-GM2 Starting Dose
  • Biological: AXO-AAV-GM2 Low Dose
  • Biological: AXO-AAV-GM2 Middle Dose
  • Biological: AXO-AAV-GM2 High Dose
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: December 8, 2020)
18
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2028
Estimated Primary Completion Date November 2024   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Male or female subjects born between 37 - 42 weeks gestation with genetically diagnosed TSD or SD mutations of either HEXA gene or HEXB gene

    a. Juvenile-onset subjects must be ≥ 2 years old and ≤ 12 years old at time of gene transfer

    i. Diagnosis consistent with juvenile-onset TSD or SD

    b. Infantile-onset subjects must be between 6-20 months of age at the time of gene transfer

    i. Diagnosis consistent with infantile-onset TSD or SD

    ii. Current or historical ability to sit without support for at least 5 seconds

  2. Surgical readiness for gene transfer by the routes of administration confirmed by the study neurosurgeon, based on examination and magnetic resonance imaging (MRI) findings
  3. Subjects receiving off-label Zavesca® (miglustat) and/or Tanganil® (acetyl-leucine) must be willing to discontinue these therapies 30 days prior to the start of screening
  4. Ability to reliably travel to the study sites for study visits according to the Schedule of Assessments
  5. Subjects must have a swallowing evaluation test performed (within 6 months) prior to administration of gene replacement therapy

Exclusion Criteria:

  1. Presence of G269S or W574C mutation
  2. History of drug-resistant seizures or status epilepticus
  3. History and/or findings of spinal cord disease that would preclude the lumbar puncture and ICM/IT infusion procedures
  4. The subject's parent(s) or legal guardian(s) is unable to understand the nature, scope, and possible consequences of the study, or does not agree to comply with the protocol defined schedule of assessments
  5. Any prior participation in a study in which a gene therapy vector or stem cell transplantation was administered
  6. Immunizations of any kind in the month prior to screening
  7. Cardiomyopathy or other cardiac disease based on echocardiogram and/or electrocardiogram, (ECG) that in the opinion of the Investigator would deem the subject unsafe to undergo surgical gene transfer
  8. Indwelling ferromagnetic devices that would preclude MRI//MRS/DTI imaging
  9. Ongoing medical condition that is deemed by the Investigator to interfere with the conduct or assessments of the study
  10. Current clinically significant infections including any requiring systemic treatment including but not limited to human immunodeficiency virus (HIV), Hepatitis A, B, or C
  11. History of or current chemotherapy, radiotherapy or other immunosuppressive therapy within the past 30 days. Corticosteroid treatment may be permitted at the discretion of the PI
  12. Clinically significant laboratory abnormalities in liver functional tests, hematology, and blood chemistry parameters
  13. Subjects for whom any of the proposed study procedures or medications would be contraindicated
  14. Failure to thrive, defined as falling 20 percentiles (20/100) in body weight in the 3 months preceding Screening/Baseline
  15. Subject is not suitable for participation in the study in the opinion of the Principal Investigator
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 6 Months to 12 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Clinical Trials 646-887-2651 patients@siogtx.com
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04669535
Other Study ID Numbers  ICMJE AXO-GM2-001
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
Plan to Share IPD: No
Responsible Party Sio Gene Therapies
Study Sponsor  ICMJE Sio Gene Therapies
Collaborators  ICMJE
  • University of Massachusetts, Worcester
  • Massachusetts General Hospital
Investigators  ICMJE
Study Director: Erika De Boever, DDS, PhD Sio Gene Therapies
PRS Account Sio Gene Therapies
Verification Date January 2021

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