SIngle-Stage, Open-Label, Safety and Efficacy Study of Adeno-Associated Virus Encoding Human Aromatic L-Amino Acid Decarboxylase by Magnetic Resonance MR-guided Infusion Into Midbrain in Pediatric Patients With AADC Deficiency
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 42
- 试验地点
- 6
- 主要终点
- Adverse events related to surgery and gene transfer
研究概览
简要总结
The overall objective of this study is to determine the safety and efficacy of AAV2-hAADC delivered to the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) in children with aromatic L-amino acid decarboxylase (AADC) deficiency.
详细描述
The Study will specifically address:
- Safety, as measured by adverse events (AEs), safety laboratory tests, brain imaging, and the relationship of AEs to study/surgical procedures or to AAV2 hAADC.
- Clinical responses to treatment with AAV2-hAADC. The primary clinical outcomes will reflect the predominant motor deficits of loss of motor function and dystonic movements.
Primary Endpoints Safety: Assessment of AE or severe AE (SAE) and its relationship to study surgery, infusion, or treatment effect (graded as definite, probable, possible, unlikely or unrelated).
- Adverse Events and Serious Adverse Events
- Post-operative MRI and/or CT (with contrast if clinically indicated)
- Clinical laboratory assessments (hematology, chemistry, immunology) Biological Activity: Demonstration of effective restoration of AADC function by assays of cerebrospinal fluid (CSF) neurotransmitter metabolites and 18-fluoro-3,4-dihydroxyphenylalanine (F-DOPA) positron emission tomography (PET) imaging.
Secondary and Exploratory Endpoints To obtain preliminary data for clinical response by assessing the magnitude and variability of changes in specific outcomes.
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
- 24 Months 至 —（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Definite diagnosis of AADC deficiency, confirmed by at least two of the following three criteria: (1) CSF neurotransmitter profile demonstrating reduced HVA and 5-HIAA, and elevated 3-OMD concentrations; (2) Plasma AADC activity less than or equal to 5 pmol/min/mL; (3) Molecular genetic confirmation of homozygous or compound heterozygous mutations in DDC.
- •Age 24 months and older.
- •Failed to derive adequate benefit from standard medical therapy (dopamine agonists, monoamine oxidase inhibitor, pyridoxine or related form of Vitamin B6), as judged by presence of residual oculugyric crises and developmental delay.
- •Documented history of motor developmental delay, with inability to walk independently without support by age 18 months.
- •Cranium sufficiently developed, with sutures closed, to enable surgical placement of SmartFrame® system on the head for MRI-guided stereotactic targeting.
- •Brain MRI does not show any conditions or malformations that are clinically significant with respect to risks for stereotactic brain surgery.
- •Parent(s)/legal guardian(s) of the subject must agree to comply with the requirements of the study, including the need for frequent and prolonged follow-up.
- •Both parents (or legal guardians) must give their consent for their child's participation in the study parents unless (i.) one parent is deceased, unknown or incompetent; (ii.) one parent is not reasonably available; or (iii.) one parent has responsibility for the care and custody of the child (if consistent with state law).
- •Baseline hematology, chemistry, and coagulation values within the normal pediatric laboratory value ranges, unless in the Investigator's judgment, the out-of-range values are not clinically significant with respect to subject's suitability for surgery.
排除标准
- •Intracranial neoplasm or any structural brain abnormality or lesion (e.g., severe brain atrophy, white matter degenerative changes), which, in the opinion of the study investigators, would confer excessive risk and/or inadequate potential for benefit.
- •Presence of other significant medical or neurological conditions that would create an unacceptable operative or anesthetic risk (including congenital heart disease, respiratory disease with home oxygen requirement, history of serious anesthesia complications during previous elective procedures, history of cardiorespiratory arrest), liver or renal failure, malignancy, or HIV positive.
- •Previous stereotactic neurosurgery.
- •Coagulopathy, or need for ongoing anticoagulant therapy.
- •Contraindication to sedation during surgery or imaging studies (SPECT, PET or MRI).
- •Receipt of any investigational agent within 60 days prior to Baseline and during study participation.
- •Evidence of clinically active infection with adenovirus or herpes virus on physical examination.
研究组 & 干预措施
Single treatment arm
Single-stage dose-escalation, open-label safety study of AAV2-hAADC delivered by image-guided convection-enhanced delivery bilaterally into the substantia nigra pars compacta and the ventral tegmental area of pediatric patients with AADC deficiency. Primary aim is to determine the dose for future studies based on safety, biomarkers of pharmacological activity of AADC and clinical outcomes. Cohort 1 (3 subjects) will receive a single low dose of AAV2 hAADC. The total AAV2-hAADC dose will be infused via MR guided infusion into 4 sites in both the left and right SNc and VTA. Dose intervals will be 90 days between the first 3 subjects. Cohort 2 dose (4 subjects) will be determined by Cohort 1 results. Following Cohort 2, Cohort 3/4 will be dose and divided divided by age. Cohorts 3/4 will receive the same dose by MR guided infusion to 1-2 sites bilaterally in-between the SNc and VTA. Cohort 5 (24-47mo old) will have same vector concentration and lower volume of infusion than Cohorts 3/4
干预措施: AAV2-hAADC (Drug)
结局指标
主要结局
Adverse events related to surgery and gene transfer
时间窗: 2 years
Assessment of adverse events related to surgery (including intracerebral hemorrhage or stroke, CNS infection) and gene transfer (including severity of post-operative dyskinesia)
CSF neurotransmitter metabolite concentrations
时间窗: 1 year
Change in CSF neurotransmitter metabolite concentrations after gene transfer (increase in homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), and elevated 3-O-methyldopa (3-OMD) concentrations)
次要结局
- Fluorodopa PET scan(Evaluated at 3 months and 2 years)
- Symptom Diary created by PI(1 years)
- Gross Motor Function Measure(2 years)
研究者
Krzysztof Bankiewicz
Professor of Neurological Surgery
Ohio State University