Aromatic L-amino Acid Decarboxylase (AADC) DeficiencyPhase 1/2AADCNCT01395641
A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC
A Phase 1/2 study testing gene therapy in people with Aromatic L-amino Acid Decarboxylase (AADC) Deficiency, run by National Taiwan University Hospital at 1 site in Taiwan.
Trial summary
This Phase I/II trial is to prove the efficacy and safety of AAV2-hAADC to treat patients with AADC deficiency. Read more about this study
- Who is it for?
- Ages 24 months and older
- Conditions the study is for
- Aromatic L-amino Acid Decarboxylase (AADC) Deficiency
- What is being tested?
- gene therapy
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteTaiwan
- Study dates
- 22 Oct 2014to 7 Mar 2022
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 24 months and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
- Classical clinical characteristics of AADC deficiency, such as oculogyric crises, hypotonia and developmental retardation.
- The sick child has to be over 2 years old or a head circumference big enough for surgery.
- Participating patients must cooperate completely for all evaluations and examinations before, during and after the whole trial.
- Parents or guardians must sign to agree on this informed consent.
Who cannot join
- Significant brain structure abnormality
- 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.
- 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.
- Subjects enrolled in this clinical trial cannot take any medications that may affect this trial.
Trial locations and contacts
1 site in 1 country.
About this study
This Phase I/II trial is to prove the efficacy and safety of AAV2-hAADC to treat patients with AADC deficiency.
Read the 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.
- Being tested
- gene therapy
- Keywords
- Aromatic Amino Acid Decarboxylase, AADC, DDC, Gene Therapy, AAV2-AADC, Viral Vector, Gene Transfer, Aromatic L-Amino Acid Decarboxylase Deficiency
- Medical subject headings
- Aromatic amino acid decarboxylase deficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
gene therapyDrug
Also called Intracerebral infusion of AAV2-hAADC viral vector
AAV2-hAADC viral vector will be injected into bilateral putamen by stereotactic surgery.
| Study group | Role | What they receive |
|---|---|---|
| Gene therapy | Experimental | Intracerebral infusion of AAV2-hAADC viral vector will be performed Receives: Drug: gene therapy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Evaluation of therapeutic effect
- At one year post-surgery, neurotransmitter metabolites (HVA or HIAA) is detectable in CSF (higher than that at pre-surgery)
- At one year post-surgery, PDMS-II score is higher than that at pre-surgery, with an improvement over 10 points
Measured: 12 months
Secondary outcomes (3)
Evaluation of safety and other therapeutic effects Evaluation for the treatment safety
- The absence of intracranial bleeding, which requires surgical management, after the surgery
- Craniotomy-induced CSF exudation
- The severity of post-surgery hyperactivity (if feeding is affected and then nasogastric tube is needed)
- Incidence of other severe adverse events (information of adverse events of all kinds and severities will be collected, including treatment-emergent adverse events).
Measured: 12 months
Evaluation of secondary therapeutic effects
- Weight gain
- Increased signal intensity of dopamine in putamen during PET imaging
- Increased score in other development evaluations
Measured: 5 years
Exploratory endpoint
- The correlation between anti-AAV2 titer and therapeutic effect
- The correlation between subject's age and therapeutic effect
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jul 2011 (estimated)
- Study start22 Oct 2014
- Primary completion18 Dec 2020
- Study completion7 Mar 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (2)Papers the sponsor has linked to this study.
- Other trials for Aromatic L-amino Acid Decarboxylase (AADC) DeficiencyStudies of the same condition, open and under way.
- More trials run by National Taiwan University HospitalThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- National Taiwan University Hospital
- Sponsor type
- University, hospital or other
- Collaborators
- PTC Therapeutics
- Responsible party
- Sponsor
- Investigators
- Wuh-Liang Hwu, M.D., Ph.D., Principal investigator, National Taiwan University Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01395641
- Sponsor's protocol ID
- NTUH-AADC-010(200802042M)
- Acronym
- AADC
- Status last verified
- Nov 2022
- First submitted
- 12 Jun 2011
- Last updated
- 10 Feb 2023
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Tai CH, Lee NC, Chien YH, Byrne BJ, Muramatsu SI, Tseng SH, Hwu WL. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022 Feb 2;30(2):509-518. doi: 10.1016/j.ymthe.2021.11.005. Epub 2021 Nov 8.
PubMed 34763085Chien 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.
PubMed 30169182
Study at a glance
From the registry record, last updated by the sponsor on 10 Feb 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I/II Clinical Trial for Treatment of Aromatic L-amino Acid Decarboxylase (AADC) Deficiency Using AAV2-hAADC
- ClinicalTrials.gov ID
- NCT01395641
- Acronym / sponsor ID
- AADC / NTUH-AADC-010(200802042M)
- Keywords
- Aromatic Amino Acid Decarboxylase, AADC, DDC, Gene Therapy, AAV2-AADC, Viral Vector, Gene Transfer, Aromatic L-Amino Acid Decarboxylase Deficiency
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- National Taiwan University HospitalUniversity, hospital or other
- Collaborators
- PTC Therapeutics
- Study start
- 22 Oct 2014 (actual)
- Primary completion
- 18 Dec 2020 (actual)
- Study completion
- 7 Mar 2022 (actual)
- First posted
- 15 Jul 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Gene therapy | Experimental | Drug: gene therapyIntracerebral infusion of AAV2-hAADC viral vector will be performed |
Who may qualify
- Ages
- 24 months and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (5 listed)
- 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.
- Classical clinical characteristics of AADC deficiency, such as oculogyric crises, hypotonia and developmental retardation.
- The sick child has to be over 2 years old or a head circumference big enough for surgery.
- Participating patients must cooperate completely for all evaluations and examinations before, during and after the whole trial.
- Parents or guardians must sign to agree on this informed consent.
Key exclusion criteria (4 listed)
- Significant brain structure abnormality
- 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.
- 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.
- Subjects enrolled in this clinical trial cannot take any medications that may affect this trial.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| gene therapyAlso: Intracerebral infusion of AAV2-hAADC viral vectorAAV2-hAADC viral vector will be injected into bilateral putamen by stereotactic surgery. | Drug | Gene therapy |
Primary outcome
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
3 secondary outcomes
Evaluation of safety and other therapeutic effects Evaluation for the treatment safety
Time frame: 12 months
Evaluation of secondary therapeutic effects
Time frame: 5 years
Exploratory endpoint
Time frame: 5 years
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 10 Feb 2023.
- Derived from this study: PubMed 34763085Tai CH, Lee NC, Chien YH, Byrne BJ, Muramatsu SI, Tseng SH, Hwu WL. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022 Feb 2;30(2):509-518. doi: 10.1016/j.ymthe.2021.11.005. Epub 2021 Nov 8.
- Derived from this study: PubMed 30169182Chien 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Wuh-Liang Hwu, M.D., Ph.D. principal investigator
National Taiwan University Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing gene therapy in people with Aromatic L-amino Acid Decarboxylase (AADC) Deficiency, run by National Taiwan University Hospital at 1 site in Taiwan.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 10 Feb 2023. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Taiwan. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Evaluation of therapeutic effect (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01395641, which also lists 2 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Feb 2023.