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Gene Transfer Clinical Trial for Mucopolysaccharidosis (MPS) IIIB (MPSIIIB)

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ClinicalTrials.gov Identifier: NCT03315182
Recruitment Status : Recruiting
First Posted : October 20, 2017
Last Update Posted : July 11, 2019
Sponsor:
Information provided by (Responsible Party):
Abeona Therapeutics, Inc

Brief Summary:
Open-label, dose-escalation clinical trial of rAAV9.CMV.hNAGLU injected intravenously through a peripheral limb vein

Condition or disease Intervention/treatment Phase
Mucopolysaccharidosis Type 3 B Biological: rAAV9.CMV.hNAGLU Phase 1 Phase 2

Detailed Description:
Adeno-associated virus serotype 9 carrying the human NAGLU gene under the control of a CMV enhancer/promoter (rAAV9.CMV.hNAGLU) will be delivered one-time through a venous catheter inserted into a peripheral limb vein.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 9 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Intervention Model Description: This is a dose escalation trial that will begin with the minimal efficacious dose as determined by preclinical studies and approved by the FDA. During the course of the trial, if safety is shown the dose will be escalated according to the clinical protocol.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase I/II Gene Transfer Clinical Trial of rAAV9.CMV.hNAGLU for Mucopolysaccharidosis (MPS) IIIB
Actual Study Start Date : October 16, 2017
Estimated Primary Completion Date : October 2020
Estimated Study Completion Date : October 2020


Arm Intervention/treatment
Experimental: Cohort 1 (Low Dose) rAAV9.CMV.hNAGLU

Subjects will receive a single infusion:

• Cohort 1 (Low Dose): 2 X 10E13 vg/kg (n=2 subjects)

Biological: rAAV9.CMV.hNAGLU
Adeno-associated virus serotype 9 carrying the human NAGLU gene under the control of a CMV enhancer/promoter (rAAV9.CMV.hNAGLU) will be delivered one-time through a venous catheter inserted into a peripheral limb vein.

Experimental: Cohort 2 (High Dose) rAAV9.CMV.hNAGLU

Subjects will receive a single infusion:

• Cohort 2 (High Dose): 5 X 10E13 vg/kg (n=4-7 subjects)

Biological: rAAV9.CMV.hNAGLU
Adeno-associated virus serotype 9 carrying the human NAGLU gene under the control of a CMV enhancer/promoter (rAAV9.CMV.hNAGLU) will be delivered one-time through a venous catheter inserted into a peripheral limb vein.




Primary Outcome Measures :
  1. Change from baseline in the Age Equivalent Developmental score (calculated by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children Second Edition, based on developmental age) compared with Natural History Study data [ Time Frame: 24 months ]
  2. Product safety as defined by the incidence, type and severity of treatment-related adverse events and serious adverse events [ Time Frame: 24 Months ]

Secondary Outcome Measures :
  1. Change from baseline of central spinal fluid heparan sulfate after treatment [ Time Frame: 24 months ]
  2. Change from baseline of plasma or urine glycosaminoglycans or heparan sulfate after treatment [ Time Frame: 24 Months ]
  3. Change from baseline in CSF or plasma NAGLU enzyme activity levels after treatment [ Time Frame: 24 Months ]
  4. Change from baseline in liver and/or spleen volumes after treatment, as measured by magnetic resonance imaging [ Time Frame: 24 Months ]
  5. Change from baseline in brain volumes after treatment, as measured by magnetic resonance imaging [ Time Frame: 24 Months ]
  6. Change from baseline in the Cognitive Age Equivalent (Developmental Age) compared to Natural History Study, calculated using the Bayley Scales of Infant and Toddler Development or the Kaufman Assessment Battery for Children [ Time Frame: 24 Months ]
  7. Change from baseline in the Adaptive Age Equivalent score after treatment compared to Natural History Study data, as assessed by parent report using the Vineland Adaptive Behavior Scale II Survey form [ Time Frame: 24 Months ]
  8. Change from baseline Developmental Quotient after treatment compared to Natural History Study data assessed by the Mullen Scales of Early Learning or the Kaufman Assessment Battery for Children. [ Time Frame: 24 Months ]
  9. Change from baseline in the Sanfilippo Behavior Rating Scale [ Time Frame: 24 Months ]
  10. Change from baseline in Pediatric Quality of Life Inventory (PedsQL™) Generic Core Scales total score [ Time Frame: 24 Months ]
  11. Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4) short form [ Time Frame: 24 Months ]
  12. Determination of vector shedding analysis in plasma, saliva, urine and feces will provide preliminary data for the Environmental Risk Assessment [ Time Frame: 24 Months ]


Information from the National Library of Medicine

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Ages Eligible for Study:   6 Months and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 6 months to 2 years or children older than 2 years with a minimum cognitive Development Quotient (DQ) of 60 or above
  • Confirmed diagnosis of MPSIIIB by both of the following two methods:

    • No detectable or significantly reduced NAGLU enzyme activity by plasma, serum, or leukocyte assay.
    • Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the NAGLU gene

Exclusion Criteria:

  • Inability to participate in the clinical evaluation as determined by Principal Investigator
  • Identification of two nonsense or null variants on genetic testing of the NAGLU gene
  • Has evidence of an attenuated phenotype of MPS IIIB
  • Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
  • Active viral infection based on clinical observations as infections by Adenoviruses, Epstein-Barr Virus, Cytomegalovirus, Respiratory Syncytial Virus
  • Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer , or precludes the child from participating in the protocol assessments and follow up as autoimmune diseases requiring immunosuppression, such as juvenile rheumatoid arthritis or idiopathic thrombocytopenia purpura
  • Subjects with total anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA binding immunoassay
  • Subjects with a positive response for the ELISPOT for T-cell responses to AAV9
  • Serology consistent with exposure to HIV, or serology consistent with active hepatitis B or C infection
  • Bleeding disorder or any other medical condition or circumstance in which a lumbar puncture (for collection of CSF) is contraindicated according to local institutional policy
  • Visual or hearing impairment sufficient to preclude cooperation with neurodevelopmental testing
  • Uncontrolled seizure disorder
  • Any item (braces, etc.) which would exclude the subject from being able to undergo MRI according to local institutional policy
  • Any other situation that precludes the subject from undergoing procedures required in this study
  • Subjects with cardiomyopathy or significant congenital heart abnormalities
  • The presence of significant non-MPS IlIB related CNS impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study
  • Abnormal laboratory values Grade 2 or higher as defined in CTCAE v4.0 for GGT, total bilirubin, creatinine, hemoglobin, WBC count, platelet count, PT and aPTT
  • Female participant who is pregnant or demonstrates a positive urine or serum result at screening assessment (if applicable).
  • Any vaccination with viral attenuated vaccines less than 30 days prior to the scheduled date of treatment (and use of prednisolone)
  • Previous treatment by Haematopoietic Stem Cell transplantation
  • Previous participation in a gene/cell therapy or ERT clinical trial

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): NCT03315182


Contacts
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Contact: Juan Ruiz, MD +34 685895069 sanfilippo@abeonatherapeutics.com

Locations
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United States, Ohio
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Federica Rinaldi, PhD    614-355-2897    federica.rinaldi@nationwidechildrens.org   
Contact: Tabatha Simmons, PhD    614-722-6921    tabatha.simmons@nationwidechildrens.org   
Principal Investigator: Kevin Flanigan, MD         
France
Armand-Trousseau Hospital Recruiting
Paris, France
Contact: Bénédicte Héron, MD    +33 (0)1 44 73 74 30    benedicte.heron@aphp.fr   
Contact: Claudia Revelli, MD       claudia.ravelli@aphp.fr   
Spain
Hospital Clinico Universitario de Santiago Recruiting
Santiago De Compostela, Spain, 15706
Contact: Maria Luz Couce, MD    +34 981 950 151    maria.luz.couce.pico@sergas.es   
Contact: Maria Jose de Castro, MD    +34 981 955 627    maria.jose.de.castro.lopez@sergas.es   
Principal Investigator: Maria Luz Couce, MD         
Sponsors and Collaborators
Abeona Therapeutics, Inc

Publications:

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Responsible Party: Abeona Therapeutics, Inc
ClinicalTrials.gov Identifier: NCT03315182     History of Changes
Other Study ID Numbers: ABT-002
First Posted: October 20, 2017    Key Record Dates
Last Update Posted: July 11, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: There is no plan to share data

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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 Abeona Therapeutics, Inc:
MPS IIIB
Sanfilippo Syndrome B
Additional relevant MeSH terms:
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Mucopolysaccharidoses
Mucopolysaccharidosis III
Carbohydrate Metabolism, Inborn Errors
Metabolism, Inborn Errors
Genetic Diseases, Inborn
Lysosomal Storage Diseases
Mucinoses
Connective Tissue Diseases
Metabolic Diseases