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

Study Status: Recruiting
Recruit Status: Recruiting
Study Type: Interventional

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 Pat

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 Summary:

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
Sponsor: Krystof Bankiewicz

Current Primary Outcome:

  • 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)


Original Primary Outcome:

  • Safety assessment of AE of SAE and its relationship to study surgery, infusion or treatment effect [ Time Frame: 2 years ]
    To assess and grade any AE and SAE and grade its relationship to study drug as definite, probable, unlikely and unrelated
  • CSF metabolites assays [ Time Frame: 2 years ]
    Assess effective improvement of biological AADC function


Current Secondary Outcome:

  • 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


Original Secondary Outcome:

  • Gross Motor Function Measure (GMFM-88) [ Time Frame: 2 years ]
    Motor function
  • Symptom Diary [ Time Frame: 2 years ]
    Frequency of oculogyric episodes
  • Pediatric Quality of Life Inventory (PedsQL) [ Time Frame: 2 years ]
    Assessment of subject disability
  • Fluorodopa PET scan [ Time Frame: 2 years ]
    Brain AADC activity evaluation


Information By: University of California, San Francisco

Dates:
Date Received: July 20, 2016
Date Started: July 2016
Date Completion: December 2020
Last Updated: August 4, 2016
Last Verified: August 2016