A Phase I/II Open Label, Single-dose, Gene Transfer Study of scAAV9.U1a.hSGSH (ABO-102) in Patients With Middle and Advanced Phases of MPS IIIA Disease
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 3
- 主要终点
- Incidence, Type and Severity of Serious Adverse Events (SAEs) by Time Frame
研究概览
简要总结
Open-label, clinical trial of scAAV9.U1a.hSGSH injected intravenously through a peripheral limb vein
详细描述
This is an open-label, single dose clinical trial. All participants will receive 3 X 10^13 vg/kg of ABO-102 delivered one time through a venous catheter inserted into a peripheral limb vein. The target population includes MPS IIIA participants with a DQ lower than 60 in middle and advanced phases of the disease. Similar numbers of MPS IIIA participants with age equivalent above and below 18 months of age will be enrolled to ensure a representation of middle and advanced phases of the disease.
This study was previously posted by Abeona Therapeutics, Inc and was transferred to Ultragenyx in August 2022.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 2 Years 至 18 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Diagnosis of MPS IIIA confirmed by the following methods:
- •No detectable or significantly reduced SGSH enzyme activity by leukocyte assay and
- •Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene
- •Cognitive Development Quotient (DQ) lower than 60 (calculated by Bayley Scales of Infant and Toddler Development - Third Edition)
- •Must be ambulatory, though may receive assistance with ambulation
- •Age range of 2 years up to 18 years (excluded)
排除标准
- •Inability to participate in the clinical evaluation as determined by Principal Investigator
- •Identification of two nonsense or null variants on genetic testing of the SGSH gene
- •At least one S298P mutation in the SGSH gene
- •Has evidence of an attenuated phenotype of MPS IIIA
- •Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
- •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, or precludes the child from participating in the protocol assessments and follow up
- •Participants with total anti-AAV9 antibody titers greater than or equal to 1:100 as determined by ELISA binding immunoassay
- •Participants 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
- •Any item (braces, etc.) which would exclude the participant from being able to undergo MRI according to local institutional policy
- •Any other situation that precludes the participant from undergoing procedures required in this study
- •Participants 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 v4.03 for GGT, total bilirubin (except in subjects diagnosed with Gilbert's syndrome), creatinine, hemoglobin, WBC count, platelet count, PT and aPTT
- •Female participant who is pregnant or demonstrates a positive urine or beta-hCG 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
- •Participants who are anticipated to undergo a procedure involving anesthesia within 6 months post- drug administration
- •Dysphagia present at Grade 3 or higher, as defined in CTCAE v4.03
研究组 & 干预措施
ABO-102
Dose of 3x10^13 vg/kg
干预措施: ABO-102 (Drug)
结局指标
主要结局
Incidence, Type and Severity of Serious Adverse Events (SAEs) by Time Frame
时间窗: From signing of informed consent through Day 60, 90, 180 and up to Day 454 (> 12 months)
An SAE is defined as any untoward medical occurrence that, at any dose: 1. Results in death 2. Is life threatening 3. Requires inpatient hospitalization or prolongation of existing hospitalization 4. Results in persistent disability/incapacity 5. Is a congenital anomaly/birth defect 6. Other situations such as important medical events that may not be immediately life threatening or result in death or hospitalization but may jeopardize the participant or may require medical or surgical intervention to prevent one of the other outcomes listed in the above definition. Relationship to study drug was defined as unrelated, unlikely, possible, probable, or definitely.
Incidence, Type and Severity of Related Treatment-Emergent Adverse Events (TEAEs) by Time Frame
时间窗: From the first dose of study drug to <30 days postdose, Day 30, 60, 90, 180 and Month 12
An adverse event (AE) is any untoward medical occurrence or unintended change from the time informed consent form (ICF) is signed, including inter-current illness that occurs during the course of a clinical trial after treatment has started, whether considered related to treatment or not. TEAEs are those that occurred after the start of study drug. Related adverse events were categorized as possible, probable, or definitely.
Change From Baseline (BL) in Multiples of Normal of Liver and Spleen Volumes After Treatment
时间窗: Baseline, Day 30, 180, Month 12
As Measured by Magnetic Resonance Imaging (MRI). Baseline value of multiple of normal is calculated using the baseline values of the Liver volume/Spleen Volume/Height and Weight. * Body Surface Area (BSA) (m2)=( Height(cm) \* Weight (kg)/3600)1/2. * Normal Liver Volume=(689.9 \* BSA (m)) - 24.7. * Normal Spleen Volume (mL)=(4.6 \* Weight (kg)) + 0.7. * Liver Volume (multiples of normal)=Subject Liver Volume (mL)/Normal Liver Volume (mL). * Spleen Volume (multiples of normal)=Subject Spleen Volume (mL)/Normal Spleen Volume (mL).
Change From BL in Cerebrospinal Fluid (CSF) Heparan Sulfate Levels After Treatment
时间窗: Baseline, Day 30, Day 180, Month 12
Change from baseline in CSF heparan sulfate levels after treatment
次要结局
- Change From Baseline in Plasma Heparan Sulfate After Treatment(Baseline, Day 30, Day 180, Month 12)
- Change From Baseline in Urine Glycosaminoglycans After Treatment(Baseline, Day 30, Day 180, Month 12)
- Change From Baseline in Urine Heparan Sulfate After Treatment(Baseline, Day 30, Day 180, Month 12)
- Change From Baseline in CSF N-Sulfoglucosamine Sulfohydrolase (SGSH) Enzyme Activity Levels After Treatment(Baseline, Day 30, Day 180, and Month 12)
- Change From Baseline in Heparan N-Sulfatase (Type A) After Treatment(Baseline, Day 30, Day 180, Month 12)
- Change From Baseline in Plasma SGSH After Treatment(Baseline, Day 30, Day 180, Month 12)
- Change From Baseline in Brain Volumes After Treatment: Average Total Cortical Thickness(Baseline, 12 months)
- Clinical Global Impression Improvement Scale at Day 180 and Month 12(Day 180, Month 12)
- Number of Participants With Abnormalities in Standard Awake 45-Minutes-Electroencephalogram (EEG) Monitoring at Baseline and Day 180(Baseline, Day 180)
- Change From Baseline in Brain Volumes After Treatment(Baseline, 12 months)
- Change From Baseline in Sleep Pattern as Measured by the Modified Children's Sleep Habits Questionnaire (CSHQ) Subscore Total After Treatment(Baseline, Day 180, Month 12)
- Change From Baseline in Parent Quality of Life, Using the Parenting Stress Index, 4th Edition (PSI-4) Total Stress Raw Score(Baseline, Day 180, Month 12)
- Change From Baseline in Gastrointestinal Symptoms Using the PedsQL™ Gastrointestinal (GI) Symptoms Scales Score(Baseline, Day 180, Month 12)
- Change From Baseline in Parent Global Impression (PGI) Total Score(Baseline, Day 180, Month 12)
- Change From Baseline in Pediatric Quality of Life Inventory (PedsQL™) Core Generic Scales Total Score(Baseline, Day 180, Month 12)
- Percent Change From Baseline in Body Mass Index After Treatment(Baseline, Day 30, Day 180, Month 12)
- Change From Baseline in Parent Symptoms Score Questionnaire(Baseline, Day 180, Month 12)
- Change From Baseline in Vector Shedding Analysis in Plasma, Saliva, Stool and Urine(Baseline, Day 30, Day 180, Month 12)