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

Primary Purpose

AADC Deficiency

Status

Recruiting

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

AAV2-hAADC

About this trial

This is an interventional treatment trial for AADC Deficiency focused on measuring AADC, gene therapy

Eligibility Criteria

4 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria

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 4 years and up.
Failed to derive adequate benefit from standard medical therapy (dopamine agonists, monoamine oxidase inhibitor, pyridoxine or related form of Vitamin B6).
Unable to ambulate independently (with or without assistive device).
Cranium sufficiently developed, with sutures closed, to enable surgical placement of SmartFrame® system on the skull 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.
Parent(s)/legal guardian(s) with custody of subject must give their consent for subject to enroll in the study.
Stable medication regimen for treatment of AADC deficiency: (i.e. no new medications introduced for at least 6 months, and no existing medication dose changes for at least 3 months prior to Baseline).
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

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.

Sites / Locations

University of California San Francisco, Benioff Children's HospitalRecruiting
Nationwide Children's HospitalRecruiting
The Ohio State University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Single treatment arm

Arm Description

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. 6 subjects will be divided in 2 groups of 3. Primary aim is to determine the dose for future studies based on safety, biomarkers of pharmacological activity of AADC and clinical outcomes. Subjects will be enrolled into 2 dose groups. Group 1 of 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. Dosing intervals will be 90 days between the first 3 subjects. Group 2 dosing level will be determined by Group 1 results.

Outcomes

Primary Outcome Measures

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)

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)

Secondary Outcome Measures

Gross Motor Function Measure

Increase in Gross Motor Function Measure-88 (GMFM-88) score

Symptom Diary created by PI

Decrease in frequency and severity of oculogyric episodes

Fluorodopa PET scan

Increase in signal in the striatum on FDOPA-PET imaging as brain AADC activity measure

Full Information

NCT ID

NCT02852213

First Posted

July 20, 2016

Last Updated

October 24, 2023

Sponsor

Krzysztof Bankiewicz

Collaborators

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

1. Study Identification

Unique Protocol Identification Number

NCT02852213

Brief Title

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

Acronym

AADC

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 Patients With AADC Deficiency

Study Type

Interventional

2. Study Status

Record Verification Date

October 2023

Overall Recruitment Status

Recruiting

Study Start Date

July 2016 (undefined)

Primary Completion Date

July 2027 (Anticipated)

Study Completion Date

July 2031 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Krzysztof Bankiewicz

Collaborators

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

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

AADC Deficiency

Keywords

AADC, gene therapy

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

31 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Single treatment arm

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

AAV2-hAADC

Other Intervention Name(s)

Adeno Virus Human Aromatic L-Amino Acid Decarboxylase

Intervention Description

Subjects will be enrolled sequentially into 2 dose groups, Group 1 followed by Group 2. Initially, up to 3 subjects initially will be enrolled in Group 1 and treated with a single dose of AAV2 hAADC (1.3x10 11 vg, delivered as an infusate volume of up to 160 μL of vector at concentration of 8.3x10 11 vg/mL) on Day 0. Enrollment in Group 2 may commence after the last subject in Group 1 is treated and followed through Month 3 post-surgery, with the approval of the data safety monitoring board (DSMB). The final safety and clinical outcome assessments will be performed 1 year post-surgery. A follow-up analysis will be performed for 2 years post-surgery. Thereafter, subjects will be enrolled in a long-term follow-up study to assess safety and clinical status updates.

Primary Outcome Measure Information:

Title

Adverse events related to surgery and gene transfer

Description

Assessment of adverse events related to surgery (including intracerebral hemorrhage or stroke, CNS infection) and gene transfer (including severity of post-operative dyskinesia)

Time Frame

2 years

Title

CSF neurotransmitter metabolite concentrations

Description

Time Frame

1 year

Secondary Outcome Measure Information:

Title

Gross Motor Function Measure

Description

Increase in Gross Motor Function Measure-88 (GMFM-88) score

Time Frame

2 years

Title

Symptom Diary created by PI

Description

Decrease in frequency and severity of oculogyric episodes

Time Frame

1 years

Title

Fluorodopa PET scan

Description

Increase in signal in the striatum on FDOPA-PET imaging as brain AADC activity measure

Time Frame

Evaluated at 3 months and 2 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

4 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria 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 4 years and up. Failed to derive adequate benefit from standard medical therapy (dopamine agonists, monoamine oxidase inhibitor, pyridoxine or related form of Vitamin B6). Unable to ambulate independently (with or without assistive device). Cranium sufficiently developed, with sutures closed, to enable surgical placement of SmartFrame® system on the skull 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. Parent(s)/legal guardian(s) with custody of subject must give their consent for subject to enroll in the study. Stable medication regimen for treatment of AADC deficiency: (i.e. no new medications introduced for at least 6 months, and no existing medication dose changes for at least 3 months prior to Baseline). 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 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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Andrea Davis, MS

Phone

614-688-6412

andrea.hesse@osumc.edu

First Name & Middle Initial & Last Name or Official Title & Degree

Waldy San Sebastian, PhD

Waldy.SanSebastian@ucsf.edu

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Krystof Bankiewicz, MD, PhD

Organizational Affiliation

OSU Professor of Neurological Surgery

Official's Role

Principal Investigator

Facility Information:

Facility Name

University of California San Francisco, Benioff Children's Hospital

City

San Francisco

State/Province

California

ZIP/Postal Code

94143

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Shivani Mahuvakar

shivani.mahuvakar@ucsf.edu

First Name & Middle Initial & Last Name & Degree

Waldy E San Sebastian, PhD

Waldy.SanSebastian@ucsf.edu

First Name & Middle Initial & Last Name & Degree

Nalin Gupta, MD

First Name & Middle Initial & Last Name & Degree

Krystof Bankiewicz, MD

Facility Name

Nationwide Children's Hospital

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43205

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Hannah Lehmann

hannah.lehmann@nationwidechildrens.org

First Name & Middle Initial & Last Name & Degree

Jeffrey Leonard, MD

Facility Name

The Ohio State University Medical Center

City

Columbus

State/Province

Ohio

ZIP/Postal Code

43221

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Andrea Davis, MS

Phone

614-688-6412

andrea.davis@osumc.edu

First Name & Middle Initial & Last Name & Degree

Russell Lonser, MD

First Name & Middle Initial & Last Name & Degree

Krystof Bankiewicz

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

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

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

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