A Single-Stage, Adaptive, Open-label, Dose Escalation Safety and Efficacy Study of AADC Deficiency in Pediatric Patients
- Registration Number
- NCT02852213
- Lead Sponsor
- Krzysztof Bankiewicz
- Brief Summary
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.
- Detailed Description
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.
The principal clinical outcome measures are:
* Motor function, as assessed by the Gross Motor Function Measure (GMFM-88)
* Frequency of oculogyric episodes, as measured by a Symptom Diary
Secondary clinical outcome measures include:
• Assessment of subject disability, as assessed using the Pediatric Evaluation of Disability Inventory (PEDI); adaptive behavior, as assessed using Vineland Adaptive Behavior Scale; Patient's Global Impression of Change (PGI-C); and quality of life, as determined using the Pediatric Quality of Life Inventory (PedsQL).
Although the investigators recognize that the utility of established developmental and cognitive assessments may be limited because of the study population's severe physical disability, the investigators will use the following:
* Peabody Developmental Motor Scales 2nd edition (PDMS-2)
* Bayley Scales of Infant Development, 3rd edition.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- All
- Target Recruitment
- 42
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Single treatment arm AAV2-hAADC 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
- Primary Outcome Measures
Name Time Method Adverse events related to surgery and gene transfer 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 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)
- Secondary Outcome Measures
Name Time Method Fluorodopa PET scan Evaluated at 3 months and 2 years Increase in signal in the striatum on FDOPA-PET imaging as brain AADC activity measure
Symptom Diary created by PI 1 years Decrease in frequency and severity of oculogyric episodes
Gross Motor Function Measure 2 years Increase in Gross Motor Function Measure-88 (GMFM-88) score
Trial Locations
- Locations (3)
University of California San Francisco, Benioff Children's Hospital
🇺🇸San Francisco, California, United States
Nationwide Children's Hospital
🇺🇸Columbus, Ohio, United States
The Ohio State University Medical Center
🇺🇸Columbus, Ohio, United States