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

February 19, 2024 updated by: Krzysztof Bankiewicz

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

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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Estimated)

42

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • California
      • San Francisco, California, United States, 94143
        • Recruiting
        • University of California San Francisco, Benioff Children's Hospital
        • Principal Investigator:
          • Nalin Gupta, MD
        • Contact:
        • Contact:
    • Ohio
      • Columbus, Ohio, United States, 43205
      • Columbus, Ohio, United States, 43221
        • Recruiting
        • The Ohio State University Medical Center
        • Principal Investigator:
          • Russell Lonser, MD
        • Contact:
        • Sub-Investigator:
          • Krystof Bankiewicz, PhD

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

4 years and older (Child, Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

Inclusion Criteria

  1. 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.
  2. Age 24 months and older.
  3. Failed to derive adequate benefit from standard medical therapy (dopamine agonists, monoamine oxidase inhibitor, pyridoxine or related form of Vitamin B6), as judged by presence of residual oculugyric crises and developmental delay.
  4. Documented history of motor developmental delay, with inability to walk independently without support by age 18 months.
  5. Cranium sufficiently developed, with sutures closed, to enable surgical placement of SmartFrame® system on the head for MRI-guided stereotactic targeting.
  6. Brain MRI does not show any conditions or malformations that are clinically significant with respect to risks for stereotactic brain surgery.
  7. 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.
  8. Both parents (or legal guardians) must give their consent for their child's participation in the study parents unless (i.) one parent is deceased, unknown or incompetent; (ii.) one parent is not reasonably available; or (iii.) one parent has responsibility for the care and custody of the child (if consistent with state law).
  9. 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

  1. 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.
  2. 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.
  3. Previous stereotactic neurosurgery.
  4. Coagulopathy, or need for ongoing anticoagulant therapy.
  5. Contraindication to sedation during surgery or imaging studies (SPECT, PET or MRI).
  6. Receipt of any investigational agent within 60 days prior to Baseline and during study participation.
  7. Evidence of clinically active infection with adenovirus or herpes virus on physical examination.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
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. Primary aim is to determine the dose for future studies based on safety, biomarkers of pharmacological activity of AADC and clinical outcomes. Cohort 1 (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. Dose intervals will be 90 days between the first 3 subjects. Cohort 2 dose (4 subjects) will be determined by Cohort 1 results. Following Cohort 2, Cohort 3/4 will be dose and divided divided by age. Cohorts 3/4 will receive the same dose by MR guided infusion to 1-2 sites bilaterally in-between the SNc and VTA. Cohort 5 (24-47mo old) will have same vector concentration and lower volume of infusion than Cohorts 3/4
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.
Other Names:
  • Adeno Virus Human Aromatic L-Amino Acid Decarboxylase

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Adverse events related to surgery and gene transfer
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)
2 years
CSF neurotransmitter metabolite concentrations
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)
1 year

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Gross Motor Function Measure
Time Frame: 2 years
Increase in Gross Motor Function Measure-88 (GMFM-88) score
2 years
Symptom Diary created by PI
Time Frame: 1 years
Decrease in frequency and severity of oculogyric episodes
1 years
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
Evaluated at 3 months and 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Krzysztof Bankiewicz

Collaborators

National Institute of Neurological Disorders and Stroke (NINDS)
University of California, San Francisco

Investigators

  • Study Director: Krystof Bankiewicz, MD, PhD, OSU Professor of Neurological Surgery

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2016

Primary Completion (Estimated)

July 1, 2027

Study Completion (Estimated)

July 1, 2031

Study Registration Dates

First Submitted

July 20, 2016

First Submitted That Met QC Criteria

July 28, 2016

First Posted (Estimated)

August 2, 2016

Study Record Updates

Last Update Posted (Estimated)

February 21, 2024

Last Update Submitted That Met QC Criteria

February 19, 2024

Last Verified

February 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 2018H0269
  • 1R01NS094292-03 (U.S. NIH Grant/Contract)
  • 5R01NS094292-07 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

The investigators will share pertinent information with the subjects care team such that standard of care for the subject can be maintained.

IPD Sharing Supporting Information Type

  • CSR

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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