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

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ClinicalTrials.gov Identifier: NCT02926066
Recruitment Status : Active, not recruiting
First Posted : October 6, 2016
Last Update Posted : November 10, 2020
Sponsor:
Information provided by (Responsible Party):
National Taiwan University Hospital

Tracking Information
First Submitted Date  ICMJE October 3, 2016
First Posted Date  ICMJE October 6, 2016
Last Update Posted Date November 10, 2020
Study Start Date  ICMJE September 2016
Estimated Primary Completion Date January 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 24, 2019)
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 5, 2016)
  • Measurable neurotransmitter metabolite HVA or HIAA levels in CSF one year after gene therapy. [ Time Frame: 13 months ]
  • Increase of PDMS-II score more than 10 points one year after gene therapy [ Time Frame: 13 months ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 24, 2019)
  • 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).
  • 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
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: October 5, 2016)
  • Post-surgery intracerebral hemorrhage [ Time Frame: 13 months ]
  • Post-surgery CSF leakage [ Time Frame: 13 months ]
  • Severity of post-gene therapy dyskinesia (if NG tube feeding is required) [ Time Frame: 13 months ]
  • Incidence of other SAE (we will collect all AEs and their severity information, including treatment-emergent adverse events) [ Time Frame: 13 months ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC - An Expansion
Official Title  ICMJE A Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC - An Expansion (NTUH-AADC-011)
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.
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 (2.37x1011 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 (2.37x1011 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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Aromatic Amino Acid Decarboxylase Deficiency
Intervention  ICMJE 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

Study Arms  ICMJE 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

Intervention: Drug: AAV2-hAADC
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: November 9, 2020)
12
Original Estimated Enrollment  ICMJE
 (submitted: October 5, 2016)
5
Estimated Study Completion Date  ICMJE January 2022
Estimated Primary Completion Date January 2022   (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, 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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE up to 6 Years   (Child)
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 NCT02926066
Other Study ID Numbers  ICMJE 201511036MIND
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party National Taiwan University Hospital
Study Sponsor  ICMJE National Taiwan University Hospital
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Yin-Hsiu Chien, MD.,PhD National Taiwan University Hospital
PRS Account National Taiwan University Hospital
Verification Date October 2020

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