An Open, Dose-escalating and Dose Confirmation Trial to Evaluate the Safety and Efficacy of VGN-R09b by Intra Putamen Injection in Patients With Severe Aromatic L-amino Acid Decarboxylase (AADC) Deficiency
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 13
- 试验地点
- 1
- 主要终点
- Number of Adverse Events (AEs), Serious Adverse Events (SAEs)
研究概览
简要总结
This trial includes dose-escalating part (phase 1) and dose confirming part, to prove the safety and efficacy of VGN-R09b to treat patients with severe AADC deficiency
详细描述
Aromatic L-amino acid decarboxylase (AADC) is an enzyme responsible for the final step in the synthesis of neurotransmitters dopamine and serotonin. AADC deficiency is a rare genetic disorder. VGN-R09b is a kind of Gene therapy with adeno-associated virus (AAV) serotype 9 (AAV9) driven human AADC (hAADC) being injected directly into putamen.
This is an open, dose-escalating and dose confirming study. The sponsor plans to explore two dose levels (6.0×1011vg and 1.28×1012vg) in dose-escalating phase (three subjects each cohort), then plans to have 10 subjects enrolled for dose confirmation phase.
This study is to give evidence for the safety and efficacy of VGN-R09b treatment for patients with severe Aromatic L-amino acid decarboxylase (AADC) deficiency.
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
- 18 Months 至 8 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •The child patient has to be ≥18 months old and < 8 years old, and a head circumference big enough for surgery as judged by investigator.
- •Historical diagnosis of AADC deficiency with clinical symptoms consistency, AND with Molecular genetic confirmation of homozygous or compound heterozygous mutation point of IVS6+4A>T in DDC gene.
- •With Plasma AADC activity less than or equal to 12 pmol/min/mL.
- •Motor development at baseline <3 months (head fully uncontrollable at baseline）, and Failed to benefit from standard medical therapy (dopamine agonists, monoamine oxidase inhibitor or related form of Vitamin B6) at discretion of investigators.
- •Parent(s)/legal guardian(s) with custody of subject must give their consent for subject to enroll in the study.
- •Parent(s)/legal guardian(s) of the subject must agree to comply with the requirements of the study, including providing disease information and support disease assessment of symptoms.
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.
- •Severe coagulopathy, or need for ongoing anticoagulant therapy.
- •clinically active infection or with severe infection within 12 weeks before screening (e.g. adenovirus or herpes virus, pneumonia, sepsis, central nervous system infection).
- •Previous stereotactic neurosurgery, or any gene/cell therapy.
- •Received live vaccination within 4 weeks.
- •Contraindication to sedation during surgery or imaging studies (PET or MRI).
研究组 & 干预措施
VGN-R09b injection
Different levels of VGN-R09b will be injected into bilateral putamen by stereotactic surgery
干预措施: VGN-R09b injection (Genetic)
结局指标
主要结局
Number of Adverse Events (AEs), Serious Adverse Events (SAEs)
时间窗: up to Week 52
Vital signs, physical examination, laboratory test will be monitored after drug injection
Number of subjects who achieved motor development milestones
时间窗: up to 24 months
Four milestones, including Head control, Sit independently, Stand/stepping with support, Walk with minimal assistant, would be assessed according to definition in Peabody Developmental Motor Scale 2nd edition (PDMS-2). Each milestone would be scored as 0, 1 or 2, and score 2 means achievement of the milestone.
次要结局
- Viral shedding(up to 1 week)
- Number of Adverse Events (AEs), Serious Adverse Events (SAEs) in Long-term follow-up(up to 5 Years)
- Change in brain AADC activity(up to 5 Years)
- Change in number of Clinical symptoms(up to 5 Years)
- Change in Cerebrospinal Fluid (CSF) neurotransmitter metabolite concentrations(up to 5 Years)
- Change from baseline in motor function(up to 5 Years)
- Immunogenicity after injection(up to 26 weeks)