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

NCT02852213 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: 2018H0269
• Study Type: interventional
• Target: 42
• Locations: 1 country
• Sites: 3

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.

Conditions

AADC Deficiency

Keywords

AADC; gene therapy

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• Gross Motor Function Measure

  2 years

• Symptom Diary created by PI

  1 years

• Fluorodopa PET scan

  Evaluated at 3 months and 2 years

Study Arms (1)

Single treatment arm

EXPERIMENTAL

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

Interventions

AAV2-hAADC DRUG

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.

Also known as: Adeno Virus Human Aromatic L-Amino Acid Decarboxylase

Single treatment arm

Eligibility Criteria

• Age: 24 Months+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 24 months and older.
• 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.
• Documented history of motor developmental delay, with inability to walk independently without support by age 18 months.
• Cranium sufficiently developed, with sutures closed, to enable surgical placement of SmartFrame® system on the head 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.
• 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).
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Krzysztof Bankiewicz: lead
• National Institute of Neurological Disorders and Stroke (NINDS): collaborator
• University of California, San Francisco: collaborator

Study Sites (3)

University of California San Francisco, Benioff Children's Hospital

San Francisco, California, 94143, United States

RECRUITING

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

RECRUITING

The Ohio State University Medical Center

Columbus, Ohio, 43221, United States

RECRUITING

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  PMID: 34253733 DERIVED

MeSH Terms

Conditions

Aromatic amino acid decarboxylase deficiency

Study Officials

• Krystof Bankiewicz, MD, PhD

  OSU Professor of Neurological Surgery

  STUDY DIRECTOR

Central Study Contacts

Andrea Davis, MS

CONTACT

614-688-6412; andrea.davis@osumc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor of Neurological Surgery

Study Record Dates

• First Submitted: July 20, 2016
• First Posted: August 2, 2016
• Study Start: July 1, 2016
• Primary Completion (Estimated): July 1, 2027
• Study Completion (Estimated): July 1, 2031
• Last Updated: October 21, 2025

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will share
• Shared Documents: CSR

Locations

US (3)