Study of AAVrh10-h.SGSH Gene Therapy in Patients With Mucopolysaccharidosis Type IIIA (MPS IIIA) (AAVance)

• ClinicalTrials.gov Identifier: NCT03612869
• Recruitment Status: Active, not recruiting
• First Posted: August 2, 2018
• Last Update Posted: August 31, 2021
• Sponsor: LYSOGENE
• Information provided by (Responsible Party): LYSOGENE

Study Description

Brief Summary:

MPS IIIA is predominantly a central nervous system disease causing cognitive disability, progressive loss of acquired skills, behavioral and sleep disturbance. LYS-SAF302 is a gene therapy which is intended to deliver a functional copy of the SGSH gene to the brain. This is a phase 2-3 study to assess the efficacy in improving or stabilizing the neurodevelopmental state of MPS IIIA patients.

Condition or disease	Intervention/treatment	Phase
Mucopolysaccharidosis Type IIIA	Drug: LYS-SAF302	Phase 2; Phase 3

Detailed Description:

The study is interventional, single arm and multi-center. Evolution under treatment will be compared to expected natural evolution based on natural history studies.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 20 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Open-label, Single-arm, Multi-center Study of Intracerebral Administration of Adeno-associated Viral (AAV) Serotype rh.10 Carrying Human N-sulfoglucosamine Sulfohydrolase (SGSH) cDNA for Treatment of Mucopolysaccharidosis Type IIIA
• Actual Study Start Date: December 17, 2018
• Estimated Primary Completion Date: March 2022
• Estimated Study Completion Date: March 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: AAV SGSH gene therapy (LYS-SAF302); One-time intracerebral administration of adeno-associated viral vector serotype rh10 containing the human N-sulfoglucosamine sulfohydrolase (SGSH) cDNA.	Drug: LYS-SAF302; Treatment will involve direct injections of the investigational product into both sides of the brain through image-guided tracks, in a single neurosurgical session.; Other Name: AAVrh10-h.SGSH

Outcome Measures

Primary Outcome Measures :

1. Change from baseline in development quotient (DQ), compared to regression reported in natural history studies [ Time Frame: Month 6, 12, 18, 24 ]
   Development Quotient will be measured for each patient using one of two standard instruments, the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) or the Kaufman Assessment Battery for Children, Second Edition (KABC-II), based on age and ability range. The development quotient (DQ) is a means to express a neurodevelopmental/cognitive delay which is computed as a ratio and expressed as a percentage using the development age (DA) score divided by the age at testing ([development age score/chronological age] × 100; range: 0 - 100, where high values are desirable).

Secondary Outcome Measures :

1. Change from baseline in the total adaptive behavior composite standard score as measured by the expanded interview Vineland Adaptive Behavior Scales (VABS-II) [ Time Frame: Month 6, 12, 18, 24 ]
   The Vineland Adaptive Behavior Scales VABS-II test measures adaptive behaviors, including the ability to cope with environmental changes, to learn new everyday skills, and to demonstrate independence. The VABS-II is a norm-based instrument, where the child's adaptive functioning is compared to that of others his or her age. The total adaptive behavior composite score describe the child's functioning. The normative mean score is 100 (normative standard deviation is 15). Higher scores indicate better functioning.
2. Change in sleep pattern as measured by the Childrens Sleep Habits Questionnaire (CSHQ) [ Time Frame: Month 6, 12, 18, 24 ]
   The Children's Sleep habits Questionnaire (CSHQ) measures sleep habits and behavioral sleep disorders in preschool and school-aged children. The abbreviated CSHQ is a 23-item multiple-choice questionnaire that is summed into 8 subscales (bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night waking, parasomnias, sleep-disordered breathing, and daytime sleepiness) and a CSHQ total score, where higher scores reflect greater disturbance in sleep pattern. Scores will be compared to scores from the Natural History control group, using the same tool and same timepoints.
3. Change from baseline in patient quality of life using the Infant and Toddler Quality of Life (ITQOL) questionnaire [ Time Frame: Month 12, 24 ]
   The 47-item ITQOL questionnaire assesses physical, mental, and social well-being of the child and the quality of life of parent/caregiver. Scores range from 0 to 100, where higher scores reflect better quality of life. Change in score from baseline will be compared to scores from the Natural History control group, using the same tool and same timepoints.
4. Change from baseline in parent quality of life, using the Parenting Stress Index, 4th Edition (PSI-4) [ Time Frame: Month 12, 24 ]
   The 36-item questionnaire (PSI-4) is used to identify parent-child problem areas, measuring 3 main domains (parental distress, parent-child dysfunctional interaction, and difficult child), which all combined form a total stress score. Higher scores reflect a higher level of stress. Change in score from baseline will be compared to scores from the Natural History control group, using the same tool and same timepoints.
5. Change from baseline in total cortical grey matter volume and white matter volume on MRI [ Time Frame: Month 12, 24 ]
   The change from baseline in grey matter and white matter volume will be assessed by magnetic resonance imaging (MRI)
6. Incidence and severity of treatment-emergent adverse events and serious adverse events throughout the study [ Time Frame: Month 24 ]
   Descriptive summary tables for the surgical period, the evaluation period, and the follow-up period will be provided.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• Documented MPS IIIA diagnosis based on genotyping confirming the SGSH gene mutations
• Cognitive DQ score on BSID-III: 50% and above

Exclusion Criteria:

• Homozygous for the S298P mutation or non-classical severe form of MPS IIIA, based on investigator's judgement.
• Participation in another gene or cell therapy clinical trial.
• Past use of SGSH enzyme replacement therapy for a period exceeding 3 months. A washout period of at least 2 months is required prior to screening.
• Current participation in a clinical trial of another investigational medicinal product.
• History of bleeding disorder or current use of medications that, in the opinion of the investigator, place them at risk of bleeding following surgery.
• Any condition that would contraindicate treatment with immunosuppressants such as tacrolimus, mycophenolate mofetil or steroids.

Contacts and Locations

Locations

United States, California

CHOC Children's

Orange, California, United States, 92868

United States, Minnesota

University of Minnesota

Minneapolis, Minnesota, United States, 55455

United States, New York

Weill Cornell Medical College

New York, New York, United States, 10065-4897

United States, Texas

Baylor college of medicine / Texas children's hospital

Houston, Texas, United States, 77030

France

Armand Trousseau Public Hospital

Paris, France, 75012

Germany

University Medical Center Hamburg-Eppendorf

Hamburg, Germany, 20246

Netherlands

Amsterdam UMC

Amsterdam, Netherlands, 1000

United Kingdom

Great Ormond Street Hospital

London, United Kingdom

Sponsors and Collaborators

LYSOGENE

More Information

Publications:

Tardieu M, Zerah M, Husson B, de Bournonville S, Deiva K, Adamsbaum C, Vincent F, Hocquemiller M, Broissand C, Furlan V, Ballabio A, Fraldi A, Crystal RG, Baugnon T, Roujeau T, Heard JM, Danos O. Intracerebral administration of adeno-associated viral vector serotype rh.10 carrying human SGSH and SUMF1 cDNAs in children with mucopolysaccharidosis type IIIA disease: results of a phase I/II trial. Hum Gene Ther. 2014 Jun;25(6):506-16. doi: 10.1089/hum.2013.238. Epub 2014 May 5.

• Responsible Party: LYSOGENE
• ClinicalTrials.gov Identifier: NCT03612869
• Other Study ID Numbers: P4-SAF-302
• First Posted: August 2, 2018
• Last Update Posted: August 31, 2021
• Last Verified: August 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by LYSOGENE:

MPS IIIA; Sanfilippo syndrome Type A; Mucopolysaccharidosis Type IIIA; Lysosomal Storage Disease

Additional relevant MeSH terms:

Mucopolysaccharidoses; Mucopolysaccharidosis III; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Metabolic Diseases