A Single-Stage, Adaptive, Open-label, Dose Escalation Safety and Efficacy Study of AADC Deficiency in Pediatric Patients (AADC)
|Study Design:||Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||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|
- Safety [ Time Frame: 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)
- Efficacy [ Time Frame: 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)
- Gross Motor Function Measure [ Time Frame: 2 years ]Increase in Gross Motor Function Measure-88 (GMFM-88) score
- Symptom Diary created by PI [ Time Frame: 1 years ]Decrease in frequency and severity of oculogyric episodes
- Fluorodopa PET scan [ Time Frame: Evaluated at 3 months and 2 years ]Increase in signal in the striatum on FDOPA-PET imaging as brain AADC activity measure
|Study Start Date:||July 2016|
|Estimated Study Completion Date:||December 2020|
|Estimated Primary Completion Date:||December 2018 (Final data collection date for primary outcome measure)|
Experimental: 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.
6 subjects will be divided in 2 groups of 3. Primary aim is to determine the dose for future studies based on safety, biomarkers of pharmacological activity of AADC and clinical outcomes.
Subjects will be enrolled into 2 dose groups. Group 1 of 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. Dosing intervals will be 90 days between the first 3 subjects. Group 2 dosing level will be determined by Group 1 results.
Subjects will be enrolled sequentially into 2 dose groups, Group 1 followed by Group 2. Initially, up to 3 subjects initially will be enrolled in Group 1 and treated with a single dose of AAV2 hAADC (1.3x10 11 vg, delivered as an infusate volume of up to 160 μL of vector at concentration of 8.3x10 11 vg/mL) on Day 0. Enrollment in Group 2 may commence after the last subject in Group 1 is treated and followed through Month 3 post-surgery, with the approval of the data safety monitoring board (DSMB).
The final safety and clinical outcome assessments will be performed 1 year post-surgery. A follow-up analysis will be performed for 2 years post-surgery. Thereafter, subjects will be enrolled in a long-term follow-up study to assess safety and clinical status updates.
Other Name: Adeno Virus Human Aromatic L-Amino Acid Decarboxylase
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT02852213
|Contact: Jill A Imamura-Ching, RN, BSN||415-476-3446||Jill.Imamura-Ching@ucsf.edu|
|Contact: Tamara L Ryan, RN||415-476-3445||Tamara.Ryan@ucsf.edu|
|United States, California|
|University of California San Francisco, Benioff Children's Hospital||Recruiting|
|San Francisco, California, United States, 94143|
|Contact: Jill A Imamura-Ching, RN, BSN 415-476-3446 Jill.Imamura-Ching@ucsf.edu|
|Contact: Tamara L Ryan, RN 415-476-3445 Tamara.Ryan@ucsf.edu|
|Principal Investigator: Nalin Gupta, MD|
|Principal Investigator: Krystof Bankiewicz, MD|
|Principal Investigator:||Krystof Bankiewicz, MD, PhD||UCSF Professor of Neurosurgery and Neurology|
|Principal Investigator:||Nalin Gupta, MD, PhD||UCSF Professor of Neurosurgery|