A Single-Stage, Adaptive, Open-label, Dose Escalation Safety and Efficacy Study of AADC Deficiency in Pediatric Patients

Study Overview
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Brief Summary
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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
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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.

Official Title
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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

Conditions
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AADC Deficiency

Intervention / Treatment
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* Drug: AAV2-hAADC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria 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 4 years and up. Failed to derive adequate benefit from standard medical therapy (dopamine agonists, monoamine oxidase inhibitor, pyridoxine or related form of Vitamin B6). Unable to ambulate independently (with or without assistive device). Cranium sufficiently developed, with sutures closed, to enable surgical placement of SmartFrame® system on the skull 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. Parent(s)/legal guardian(s) with custody of subject must give their consent for subject to enroll in the study. Stable medication regimen for treatment of AADC deficiency: (i.e. no new medications introduced for at least 6 months, and no existing medication dose changes for at least 3 months prior to Baseline). 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. Exclusion Criteria 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.

Ages Eligible for Study
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Minimum Age: 4 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single treatment arm<br>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. | Drug: AAV2-hAADC<br>* 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.<br>* Other names: Adeno Virus Human Aromatic L-Amino Acid Decarboxylase;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events related to surgery and gene transfer | Assessment of adverse events related to surgery (including intracerebral hemorrhage or stroke, CNS infection) and gene transfer (including severity of post-operative dyskinesia) | 2 years | 
| CSF neurotransmitter metabolite concentrations | 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) | 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gross Motor Function Measure | Increase in Gross Motor Function Measure-88 (GMFM-88) score | 2 years | 
| Symptom Diary created by PI | Decrease in frequency and severity of oculogyric episodes | 1 years | 
| Fluorodopa PET scan | Increase in signal in the striatum on FDOPA-PET imaging as brain AADC activity measure | Evaluated at 3 months and 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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AADC, gene therapy