A Study of SmartFlow® Magnetic Resonance (MR) Compatible Ventricular Cannula for Administering Eladocagene Exuparvovec to Pediatric Participants

Study Overview
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Brief Summary
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This study will have a trial phase, extension phase, and a long-term extension phase. The primary objectives of the trial phase are to assess the pharmacodynamics (PD) of eladocagene exuparvovec treatment by evaluation of homovanillic acid (HVA) levels and to assess the safety of the SmartFlow® magnetic resonance (MR) Compatible Ventricular Cannula for administering eladocagene exuparvovec to pediatric participants with aromatic L-amino acid decarboxylase (AADC) deficiency. The extension phase is designed to capture additional clinical information for eladocagene exuparvovec through study evaluations, changes in motor development, AADC-specific symptoms, and other PD measures. The long-term extension phase is designed to capture long-term safety and efficacy data from participants treated with eladocagene exuparvovec.

Official Title
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An Open-Label Trial to Address the Safety of the SmartFlow MR-Compatible Ventricular Cannula for Administering Eladocagene Exuparvovec to Pediatric Subjects

Conditions
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AADC Deficiency

Intervention / Treatment
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* Genetic: Eladocagene Exuparvovec


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pediatric participants must have genetically-confirmed AADC deficiency with typical clinical characteristics and decreased AADC enzyme activity in plasma. Cranium sufficiently developed to allow placement of ClearPoint® system for stereotactic surgery. Persistent neurological defects secondary to AADC deficiency despite standard medical therapy (dopamine agonists, monoamine oxidase inhibitor, pyridoxine, or other forms of vitamin B6) in the opinion of the investigator. Unable to ambulate independently (with or without assistive device). Baseline hematology, chemistry, and coagulation values within the normal pediatric laboratory value ranges, unless in the investigator's opinion the out of range values are not clinically significant with respect to the participant's suitability for surgery. Participant must test negative for coronavirus disease of 2019 (COVID-19) a maximum of 72 hours prior to receiving gene therapy. Participant must be on stable dosage for 3 months prior to baseline for all medications related to treatment of AADC deficiency, including dopamine agonists, monoamine oxidase inhibitors, anticholinergic drugs, and vitamin B6. Females of childbearing potential must have a negative pregnancy test at screening and baseline and agree to abstinence or double-barrier form of contraception for the duration of the study following discharge from the hospital (acceptable methods will be determined by the site). Males sexually active with females of childbearing potential must agree to use a barrier method of birth control during the study following discharge from the hospital. Parent(s)/legal guardian(s) of the participant 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 the participant must give their consent for the participant to enroll in the study. Exclusion Criteria: The participant has presence of other significant medical or neurological conditions that would create an unacceptable operative or anesthetic risk. Participants with pyridoxine 5'-phosphate oxidase or tetrahydrobiopterin (BH4) deficiency. Contraindication for imaging studies (computed tomography [CT] scan, PET, or magnetic resonance imaging [MRI]), including sedation limitations or metal that would interfere with a brain MRI. Anti-adeno-associated virus, serotype 2 (anti-AAV2) antibody titer higher than 1:1200 or >1 optical density value by enzyme-linked immunosorbent assay. Participants who have received treatment with other experimental therapies within the last 24 weeks prior to planned gene therapy administration, or any treatment ever with a gene therapy. Evidence of a clinically active infection. Females who are pregnant or breast feeding.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 17 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: Eladocagene Exuparvovec<br>Participants will receive eladocagene exuparvovec intraoperatively at 1.8×10^11 vector genomes (vg) via SmartFlow® MR Compatible Ventricular Cannula in a single operative session. Participants will receive standard of care for their AADC deficiency during the study. | Genetic: Eladocagene Exuparvovec<br>* Four 0.08 milliliters (mL) infusions at a dose of 0.45×10^11 vg and a volume of 80 microliters (μl) per site to 4 sites (2 per putamen), for the total dose of 1.8×10^11 vg and a total volume of 320 μl per participant.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in HVA Metabolite Levels at the End of the Trial Phase |  | Baseline (Day 1), Week 8 | 
| Number of Participants With Adverse Events (AEs) Associated With the Surgical Administration of Eladocagene Exuparvovec Using the SmartFlow® MR-Compatible Ventricular Cannula |  | Baseline (Day 1) up to Week 8 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Neurotransmitter Cerebrospinal Fluid (CSF) Metabolite HVA at Week 48 |  | Baseline (Day 1), Week 48 | 
| Change From Baseline in Positron Emission Tomography (PET) Imaging of Putaminal-Specific L-6-[18F] Fluoro-3,4-Dihydroxyphenylalnine (18F-DOPA) PET Uptake at the End of the Trial Phase (Week 8) and the Extension Phase (Week 48) |  | Baseline (Day 1), Week 8, Week 48 | 
| Change From Baseline in Neurotransmitter CSF Metabolites 5-hydroxyindoleacetic acid (5-HIAA), and 3-O-methyldopa (3-OMD) at Weeks 8 and 48 |  | Baseline (Day 1), Weeks 8 and 48 | 
| Number of Participants who Attain Motor Milestones |  | Baseline (Day 1) up to Week 260 | 
| Change in Peabody Developmental Motor Scale, Second Edition (PDMS-2) |  | Baseline (Day 1), Week 260 | 
| Change in Bayley Scale of Infant Development, Third Edition (Bayley-III) |  | Baseline (Day 1), Week 260 | 
| Change in EuroQol-5 Dimensions Youth Version (EQ-5D-Y) |  | Baseline (Day 1), Week 260 | 
| Change in Body Weight |  | Baseline (Day 1), Week 260 | 
| Number of Participants With AADC-Specific Symptoms |  | Baseline (Day 1) up to Week 260 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) |  | Baseline (Day 1) up to Week 260 | 

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