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A Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC - An Expansion

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02926066
Recruitment Status : Completed
First Posted : October 6, 2016
Last Update Posted : February 10, 2023
Sponsor:
Collaborator:
PTC Therapeutics
Information provided by (Responsible Party):
National Taiwan University Hospital

Study Description
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Brief Summary:
This clinical trial expansion is to offer patients, who are not enrolled into the Phase I/II trial, a chance of treatment, to provide the experience in this gene therapy, and to increase the dose slightly.

Condition or disease Intervention/treatment Phase
Aromatic Amino Acid Decarboxylase Deficiency Drug: AAV2-hAADC Phase 2

Detailed Description:

AAV2-hAADC will be made by a GMP laboratory. An MRI will be performed to define the brain structure, and then metal nails will be fixed on the skull and a CT will be performed. The two images will be confined and the direction and depth of infusion will be determined. During the surgery, a stereotactic device will be implanted on both sides of the brain on a bur hole. Each putamen will be injected for two times. If there is no complication from the surgery, the patients will enter the follow up period.

In Cohort 1, subjects for high dose (2.37x10^11 vg) will be enrolled via sequential enrollment with an observation for 2 months or even longer. Only after a subject passing peak dyskinesia, which is indicated by a reduced drug dose required for alleviation of dyskinesia, or improved food intake, and being verified by Safety Committee, treatment for the next patient with high dose can be proceeded.

In Cohort 2, in order to be compared with Phase I/II (n=10), 4 patients will be treated in Cohort 2 and all of them will use the high dose (2.37x10^11 vg). Patients older than 3 (no more than 2 patients) years of age will be enrolled via sequential enrollment with an observation for 2 months or longer. Only after a subject passing peak dyskinesia, which is indicated by a reduced drug dose required for alleviation of dyskinesia, or improved food intake, which has been verified by the Safety Committee can the treatment at a high dose begin in the next patient older than 3.

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC - An Expansion (NTUH-AADC-011)
Actual Study Start Date : November 9, 2016
Actual Primary Completion Date : January 24, 2022
Actual Study Completion Date : May 16, 2022

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: AAV2-hAADC

Dosage form: Aqueous solution Dose(s): 2.37x10^11 vg/case(High dose) Dosing schedule: Intracerebral infusion, single dose Mechanism of action (if known): supplement a gene defect

Dosage form: Aqueous solution Dose(s): 1.81x10^11 vg/case(Standard dose) Dosing schedule: Intracerebral infusion, single dose Mechanism of action (if known): supplement a gene defect

 Drug: AAV2-hAADC

Dosage form: Aqueous solution Dose(s): 2.37x10^11 vg/case(High dose) Dosing schedule: Intracerebral infusion, single dose Mechanism of action (if known): supplement a gene defect

Dosage form: Aqueous solution Dose(s): 1.81x10^11 vg/case(Standard dose) Dosing schedule: Intracerebral infusion, single dose Mechanism of action (if known): supplement a gene defect


Outcome Measures
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Primary Outcome Measures :
  1. Evaluation of therapeutic effect [ Time Frame: 13 months ]
    1. At one year post-surgery, neurotransmitter metabolites (HVA or HIAA) increased in the CSF (compared to the pre-surgery (Baseline) level).
    2. At one year post-surgery, PDMS-II score is higher than that at pre-surgery (Baseline), with an improvement over 10 points.


Secondary Outcome Measures :
  1. Evaluation for the treatment safety [ Time Frame: 13 months ]
    1. The absence of intracranial bleeding, which requires surgical management, after the surgery
    2. Craniotomy-induced CSF exudation
    3. The severity of post-surgery dyskinesia (if feeding is affected and then nasogastric tube is required)
    4. Incidence of other severe adverse events (information of adverse events of all kinds and severities will be collected, including treatment-emergent adverse events).

  2. Evaluation of secondary therapeutic effects [ Time Frame: 13 months ]
    1. Weight gain
    2. Increased signal intensity of dopamine in putamen during PET imaging
    3. Increased score in other development evaluations

  3. Exploratory endpoint [ Time Frame: 13 months ]
    1. The correlation between AAV2 antibody titer and therapeutic effect
    2. The correlation between subject's age and therapeutic effect


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 6 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. With a confirmed diagnosis of AADC, including cerebrospinal fluid analysis to show reduced levels of neurotransmitter metabolites, HVA and 5-HIAA, and higher L-Dopa, or with more than one mutation within AADC gene, etc.
  2. Classical clinical characteristics of AADC deficiency, such as oculogyric crises, hypotonia and developmental retardation.
  3. The child patient has to be over 2 years old or a thickness of skull enough for surgery.
  4. The child patient has to be under 6 years old (72 months) before being treated with study drugs.
  5. Participating patients must cooperate completely for all evaluations and examinations before, during and after the whole trial.
  6. Parents or guardians must sign to agree on this informed consent.

Exclusion criteria:

  1. Significant brain structure abnormality determined by the physician.
  2. Patients with any health or neurological doubts that may increase the risk of surgery cannot join this trial. PI has the right to evaluate the feasibility of subjects for this trial based on his/her health condition.
  3. Patients with anti-AAV2 neutralizing antibody titer over 1,200 folds or an ELISA OD over 1 cannot be recruited into this trial.
  4. Subjects participating in this trial cannot take any medications that may affect this clinical trial, which do not apply to those drugs used at specified duration as mentioned in this protocol.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02926066


Locations
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Taiwan
National Taiwan University Hospital
Taipei, Taiwan, 100
Sponsors and Collaborators
National Taiwan University Hospital
PTC Therapeutics
Investigators
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Principal Investigator: Yin-Hsiu Chien, MD.,PhD National Taiwan University Hospital
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: National Taiwan University Hospital
ClinicalTrials.gov Identifier: NCT02926066    
Other Study ID Numbers: 201511036MIND
First Posted: October 6, 2016    Key Record Dates
Last Update Posted: February 10, 2023
Last Verified: November 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by National Taiwan University Hospital:
Aromatic L-amino acid decarboxylase (AADC)