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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 : October 20, 2017
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 October 20, 2017
Actual Study Start Date  ICMJE October 1, 2014
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 16, 2017)
Efficacy of the intervention [ Time Frame: 13 months ]
  1. Measurable neurotransmitter metabolite HVA or HIAA levels in CSF one year after gene therapy.
  2. Increase of PDMS-II score more than 10 points one year after gene therapy
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 Complete list of historical versions of study NCT01395641 on Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: May 16, 2017)
Safety of the trial [ Time Frame: 12 months ]
  1. Post-surgery intracerebral hemorrhage
  2. Post-surgery CSF leakage
  3. Severity of post-gene therapy dyskinesia (if NG tube feeding is required)
  4. Incidence of other SAE (we will collect all AEs and their severity information, including treatment-emergent adverse events)
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
 (submitted: May 16, 2017)
  • Other secondary efficacy endpoints [ Time Frame: 13 months ]
    1. Body weight gain
    2. Increase putaminal signal in F-DOPA PET study
    3. Increase of score in other developmental tests
  • Exploratory endpoint [ Time Frame: 13 months ]
    1. Correlation between anti-AAV2 titer and efficacy
    2. Correlation between age and efficacy
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 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, 2020
Estimated Primary Completion Date December 31, 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. A definitive diagnosis of AADC deficiency, including a CSF study showing decreased levels of HVA and 5-HIAA, and an elevated L-dopa level, and the presence of at least one AADC gene pathologic mutation.
  2. Typical clinical manifestations of the disease, such as oculogyric crisis, hypotonia and delayed development.
  3. Over 2 years of age, or has skull bones suitable for surgery.
  4. Participating patient must be fully cooperative for assessments and tests conducted before and throughout the entire trial.
  5. The parents or guardians must sign the Informed Consent Form to give their consent.

Exclusion criteria

  1. Obvious brain structural change in the judgment of the investigator.
  2. The subject will be excluded if there is any health or neurological concern which might increase the risk of surgery. The principal investigator has the right to assess whether the subject is eligible for this trial based on the subject's health condition.
  3. Patients with anti-AAV2 antibody titer higher than 1,200, or >1 O.D. value by ELISA will be excluded.
  4. Subject participating in this trial must not take any drug that might compromise this clinical 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
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, MD Department of Pediatrics and Medical Genetics, National Taiwan University Hospital
PRS Account National Taiwan University Hospital
Verification Date May 2017

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