NCT02852213

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

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

• Status: Recruiting
• Phase: Phase 1
• Study type: Interventional
• Enrollment: 42 (estimated)
• Sponsor: Krzysztof Bankiewicz · Academic / Other
• Sex: All
• Age: 24 Months
• Healthy volunteers: Not accepted

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.

Conditions

• AADC Deficiency

Interventions

Type	Name	Description
DRUG	AAV2-hAADC	Initially, subjects will be enrolled sequentially into 2 dose groups. 3 subjects will be enrolled in Cohort 1 and treated with a single dose of AAV2 hAADC (1.3x10 11 vg, delivered as infusate volume of up to 160μL of vector at concentration of 8.3x10 11 vg/mL) on Day 0. Enrollment in Cohort 2 may commence after the last subject in Cohort 1 is treated and followed through Month 3 post-op, with approval of the data safety monitoring board (DSMB). Cohort 2 will receive a higher dose (4.2 x 10\^11 vg, 160 uL). Upon DSMB review of Cohort 1/2 results, Cohort 3 (4-12 yo) and 4 (aged \>/= 13 yo) will be dosed (1.6 x 10\^12 vg, 60uL) in 1-2 sites bilaterally in-between the SNc and VTA. Cohort 5 will follow (aged 24-47 months) at 1.3 x 10\^12 vg, 500uL. Final safety and clinical outcome assessments will be performed 1 year post-surgery. Follow-up analysis will be performed for 2 years post-op. Subjects will be enrolled in a long-term follow-up study to assess safety and clinical status updates.

Timeline

• Start date: 2016-07-01
• Primary completion: 2027-07-01
• Completion: 2031-07-01
• First posted: 2016-08-02
• Last updated: 2025-10-21

Locations

3 sites across 1 country: United States

Regulatory

• FDA-regulated drug study