Phase I/II Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH

Tracking Information
First Submitted Date ICMJE	March 17, 2016
First Posted Date ICMJE	March 23, 2016
Last Update Posted Date	March 1, 2018
Study Start Date ICMJE	March 2016
Estimated Primary Completion Date	December 2019 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: March 17, 2016)	Development of unacceptable toxicity: [ Time Frame: 24 months ]; Determination of safety based on the development of unacceptable toxicity: defined as the occurrence of two or more unanticipated Grade III or higher treatment-related toxicity.
Original Primary Outcome Measures ICMJE	Same as current
Change History	Complete list of historical versions of study NCT02716246 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: February 27, 2018)	Reduction of CSF or urine glycosaminoglycans or heparan sulfate at 6 and/or 12 months after treatment [ Time Frame: 12 months ]; Increase in CSF or plasma or leukocyte SGSH enzyme activity levels at 6 and/or 12 months [ Time Frame: 12 months ]; Reduced liver and/or spleen volumes at 6 and/or 12 months after treatment, as measured by magnetic resonance imaging (MRI) [ Time Frame: 12 months ]; Improved adaptive functioning, or arrest of decline in adaptive functioning at 6 and/or 12 months, as assessed by parent report using the Vineland Adaptive Behavior Scale [ Time Frame: 12 months ]; Improved cognitive ability or arrest of cognitive deterioration at 6 and/or 12 months after treatment, as measured by direct testing of the child using the Leiter International Performance Scale [ Time Frame: 12 months ]; Improved cognitive ability or arrest of cognitive deterioration at 6 and/or 12 months after treatment, as measured by direct testing of the child using the Mullen Scales of Early Learning [ Time Frame: 12 months ]; Improved cognitive ability or arrest of cognitive deterioration at 6 and/or 12 months after treatment, as measured by direct testing of the child using the Sanfilippo Behavior Rating Scale [ Time Frame: 12 months ]
Original Secondary Outcome Measures ICMJE; (submitted: March 17, 2016)	Increase in CSF and blood leukocyte SGSH enzyme activity levels at 6 and/or 12 months [ Time Frame: 12 months ]; Reduced liver and spleen volumes at 6 and/or 12 months after treatment, as measured by magnetic resonance imaging (MRI) [ Time Frame: 12 months ]; Improved adaptive functioning, or arrest of decline in adaptive functioning at 6 and/or 12 months, as assessed by parent report using the Vineland Adaptive Behavior Scale [ Time Frame: 12 months ]; Improved cognitive ability or arrest of cognitive deterioration at 6 and/or 12 months after treatment, as measured by direct testing of the child using the Leiter International Performance Scale and the Mullen Scales of Early Learning [ Time Frame: 12 months ]; Reduction of urine glycosaminoglycans or heparan sulfate at 6 and/or 12 months after treatment [ Time Frame: 12 months ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Phase I/II Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH
Official Title ICMJE	Phase I/II Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH for Mucopolysaccharidosis (MPS) IIIA
Brief Summary	Open-label, dose-escalation clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein
Detailed Description	Self-complementary adeno-associated virus serotype 9 carrying the human SGSH gene under the control of a U1a promoter (scAAV9.U1a.hSGSH) will be delivered one time through a venous catheter inserted into a peripheral limb vein. The vector will be delivered undiluted over 5 to 50 minutes, under light to moderate sedation as needed. Dosing volume will be approximately 0.5 to 3 mL/kg, depending on final vector product concentration and subject cohort. A tapering course of prophylactic enteral prednisone or prednisolone will be administered
Study Type ICMJE	Interventional
Study Phase	Phase 1; Phase 2
Study Design ICMJE	Allocation: Non-Randomized; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Mucopolysaccharidosis Type 3 A Sanfilippo Syndrome
Intervention ICMJE	Biological: scAAV9.U1a.hSGSH; Self-complementary adeno-associated virus serotype 9 carrying the human SGSH gene under the control of a U1a promoter (scAAV9.U1a.hSGSH) will be delivered one time through a venous catheter inserted into a peripheral limb vein.
Study Arms	Experimental: Cohort 1 Low Dose Open-label, dose-escalation clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein • Cohort 1 (Low Dose): 0.5 X 10^13 vg/kg (n=3 subjects) Intervention: Biological: scAAV9.U1a.hSGSH; Experimental: Cohort 2 Mid Dose Open-label, dose-escalation clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein • Cohort 2 (Mid Dose): 1 X 10^13 vg/kg (n=3 subjects) Intervention: Biological: scAAV9.U1a.hSGSH; Experimental: Cohort 3 High Dose Open-label, dose-escalation clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein • Cohort 3 (High Dose): 3 X 10^13 vg/kg (n=9-12 subjects) Intervention: Biological: scAAV9.U1a.hSGSH
Publications *	Duncan FJ, Naughton BJ, Zaraspe K, Murrey DA, Meadows AS, Clark KR, Newsom DE, White P, Fu H, McCarty DM. Broad functional correction of molecular impairments by systemic delivery of scAAVrh74-hSGSH gene delivery in MPS IIIA mice. Mol Ther. 2015 Apr;23(4):638-47. doi: 10.1038/mt.2015.9. Epub 2015 Jan 16.
* 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: November 27, 2017)	16
Original Estimated Enrollment ICMJE; (submitted: March 17, 2016)	9
Estimated Study Completion Date	December 2020
Estimated Primary Completion Date	December 2019 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Age 6 months old or greater; Confirmed diagnosis of MPS IIIA by either of two methods:; No detectable or significantly reduced* SGSH enzyme activity by leukocyte or fibroblast assay.; Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene; Clinical history or examination features of neurologic dysfunction Exclusion Criteria: Inability to participate in the clinical evaluation as determined by PI; Identification of two nonsense or null variants on genetic testing of the SGSH gene, as judged by the principal investigator; Has evidence of an attenuated phenotype of MPS IIIA, as judged by the principal investigator; Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics; Inability to be safely sedated in the opinion of the clinical anesthesiologist; Active viral infection based on clinical observations; Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer; Subjects with anti-AAV9 antibody titers ≥ 1:100 as determined by ELISA binding immunoassay; 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, due to the requirement for multiple MRI examinations as part of the study protocol. Subjects who are stable on anticonvulsive medications may be included; Any item (braces, etc.) which would exclude the patient from being able to undergo MRI according to local institutional policy; Any other situation that would exclude the patient from undergoing any other procedure required in this study; Patients with cardiomyopathy or significant congenital heart abnormalities; The presence of significant non-MPS IlIA 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 bhCG result at screening assessment (if applicable). Due to the nature of enzyme activity testing, normal ranges and reported units vary from lab to lab. Many laboratories utilize control samples rather than normal ranges, to account for the influence of small day-to-day fluctuations in the laboratory environment. For the purposes of invitation to a screening visit, we will accept "significantly reduced" results as those interpreted as such by any clinical laboratory approved to perform this diagnostic test. For uniformity of data for analysis, and confirmation of accurate diagnosis before gene transfer, subjects who consent to complete the screening visit will have their blood drawn for confirmatory enzyme activity level to be performed by Greenwood Genetics Center Biochemical Laboratory. Subjects must have an enzyme activity level considered to be in the affected range by Greenwood Genetic Center Biochemical Laboratory to proceed within the study.
Sex/Gender	Sexes Eligible for Study: All
Ages	6 Months and older (Child, Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact: Krista Kunkler 614-722-2238 krista.kunkler@nationwidechildrens.org Contact: Tabatha Simmons, PhD 614-722-6921 tabatha.simmons@nationwidechildrens.org
Listed Location Countries ICMJE	Australia, Spain, United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT02716246
Other Study ID Numbers ICMJE	ABT001
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	Plan to Share IPD: No Plan Description: There is no plan to share data
Responsible Party	Abeona Therapeutics, Inc
Study Sponsor ICMJE	Abeona Therapeutics, Inc
Collaborators ICMJE	Not Provided
Investigators ICMJE	Principal Investigator: Kevin Flanigan, MD Nationwide Children's Hospital
PRS Account	Abeona Therapeutics, Inc
Verification Date	February 2018
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP