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A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC (AADC)

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. Identifier: NCT01395641
Recruitment Status : Active, not recruiting
First Posted : July 15, 2011
Last Update Posted : August 11, 2021
Information provided by (Responsible Party):
National Taiwan University Hospital

Tracking Information
First Submitted Date  ICMJE June 12, 2011
First Posted Date  ICMJE July 15, 2011
Last Update Posted Date August 11, 2021
Actual Study Start Date  ICMJE October 1, 2014
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 4, 2021)
Evaluation of therapeutic effect [ Time Frame: 12 months ]
  1. At one year post-surgery, neurotransmitter metabolites (HVA or HIAA) is detectable in CSF (higher than that at pre-surgery)
  2. At one year post-surgery, PDMS-II score is higher than that at pre-surgery, with an improvement over 10 points
Original Primary Outcome Measures  ICMJE
 (submitted: July 14, 2011)
post-operative intracerebral bleeding [ Time Frame: Post-operative day 0 (CT) and day 3 (MRI) ]
Number of patients with detectable intracerebral bleeding Number of patients with serious intracerebral bleeding that requires surgical management
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 4, 2021)
  • Evaluation of safety and other therapeutic effects Evaluation for the treatment safety [ Time Frame: 12 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 hyperactivity (if feeding is affected and then nasogastric tube is needed)
    4. Incidence of other severe adverse events (information of adverse events of all kinds and severities will be collected, including treatment-emergent adverse events).
  • Evaluation of secondary therapeutic effects [ Time Frame: 5 years ]
    1. Weight gain
    2. Increased signal intensity of dopamine in putamen during PET imaging
    3. Increased score in other development evaluations
  • Exploratory endpoint [ Time Frame: 5 years ]
    1. The correlation between anti-AAV2 titer and therapeutic effect
    2. The correlation between subject's age and therapeutic effect
Original Secondary Outcome Measures  ICMJE
 (submitted: July 14, 2011)
  • Motor development [ Time Frame: 12th month post surgery ]
    Number of patients showing improvement of PDMS-2 score
  • CSF neurotransmitter [ Time Frame: 12th month post surgery ]
    Number of patients showing an increase in CSF neurotransmitter concentration
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC
Official Title  ICMJE A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC
Brief Summary This Phase I/II trial is to prove the efficacy and safety of AAV2-hAADC to treat patients with AADC deficiency.
Detailed Description

Aromatic L-amino acid decarboxylase (AADC) is an enzyme responsible for the final step in the synthesis of neurotransmitters dopamine and serotonin. AADC deficiency is a rare genetic disorder. Taiwanese carry a high prevalence of AADC deficiency due to the founder mutation IVS6+4 A>T, and patients usually die before the age 5-6 years due to severe motor dysfunction.

Gene therapy with adeno-associated virus (AAV) serotype 2 (AAV2) driven human AADC (hAADC) has been tested in both animal models and Phase I clinical trials of Parkinson disease. We have done a compassionate treatment of 8 patients with AADC deficiency by AAV2-hAADC and demonstrated a result that among the treated patients, 4 could stand with support, 3 could sit with support, and there was no virus-associated toxicity. The longest follow up has exceeded 4 years.

This study is to prove the safety and efficacy of AAV2-hAADC treatment for patients with Aromatic L-amino acid decarboxylase (AADC) deficiency.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Aromatic L-amino Acid Decarboxylase (AADC) Deficiency
Intervention  ICMJE Drug: gene therapy
AAV2-hAADC viral vector will be injected into bilateral putamen by stereotactic surgery.
Other Name: Intracerebral infusion of AAV2-hAADC viral vector
Study Arms  ICMJE Experimental: Gene therapy
Intracerebral infusion of AAV2-hAADC viral vector will be performed
Intervention: Drug: gene therapy
Publications * Chien YH, Lee NC, Tseng SH, Tai CH, Muramatsu SI, Byrne BJ, Hwu WL. Efficacy and safety of AAV2 gene therapy in children with aromatic L-amino acid decarboxylase deficiency: an open-label, phase 1/2 trial. Lancet Child Adolesc Health. 2017 Dec;1(4):265-273. doi: 10.1016/S2352-4642(17)30125-6. Epub 2017 Oct 23.

*   Includes publications given by the data provider as well as publications identified by Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 14, 2011)
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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, together with more than one mutation within AADC gene.
  2. Classical clinical characteristics of AADC deficiency, such as oculogyric crises, hypotonia and developmental retardation.
  3. The sick child has to be over 2 years old or a head circumference big enough for surgery.
  4. Participating patients must cooperate completely for all evaluations and examinations before, during and after the whole trial.
  5. Parents or guardians must sign to agree on this informed consent.

Exclusion criteria

  1. Significant brain structure abnormality
  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. Since high-level neutralizing antibodies may disturb the therapeutic effect of gene therapy, patients with anti-AAV2 neutralizing antibody titer over 1,200 folds or an ELISA OD over 1 cannot be enrolled into this trial.
  4. Subjects enrolled in this clinical trial cannot take any medications that may affect this trial.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 24 Months and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Taiwan
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT01395641
Other Study ID Numbers  ICMJE NTUH-AADC-010(200802042M)
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Taiwan University Hospital
Study Sponsor  ICMJE National Taiwan University Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Wuh-Liang Hwu, M.D., Ph.D. National Taiwan University Hospital
PRS Account National Taiwan University Hospital
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP