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AADC Gene Therapy for Parkinson's Disease

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ClinicalTrials.gov Identifier: NCT02418598
Recruitment Status : Recruiting
First Posted : April 16, 2015
Last Update Posted : February 28, 2018
Sponsor:
Collaborators:
Takara Bio Inc.
Gene Therapy Research Institution,Co.,Ltd.
Information provided by (Responsible Party):
Shinichi Muramatsu, Jichi Medical University

Brief Summary:
The purpose of this study is to evaluate the safety, efficacy of intra-putaminal infusion of AAV-hAADC-2 (adeno-associated virus encoding human aromatic L-amino acid decarboxylase) by stereotaxic surgery in patients with advanced Parkinson's disease.

Condition or disease Intervention/treatment Phase
Parkinson Disease Genetic: Cohort1 Genetic: Cohort2 Phase 1 Phase 2

Detailed Description:

Subjects will be hospitalized and conducted the baseline examination on Day -10. The target putamen for AAV-hAADC-2 infusion is identified on MRI image that has been taken prior to the operation, and then subjects will be bilaterally infused with a total volume of 200 / 600 µL at a total of 4 sites (2 sites in left putamen, 2 sites in right putamen; 50 / 150 µL per site) at a flow rate of 3 µL per minute on Day 0.

After the infusion is complete, the cannula devices will be removed, and the surgical incision will be seamed in accordance with usual trephination. After that, cranial CT scan will be performed so as to confirm whether there are complications such as the occurrence of intracranial bleeding or not. Subjects stay in a hospital for 14 days after infusion of AAV-hAADC-2.

Data and Safety Monitoring Board (DSMB) will be evaluated the safety and efficacy of all subjects at 6 months later assessment in low dose cohort. If there are no events relevant to the discontinuance criteria or moderate to severe adverse events with casual relationship, "Definitely related" or "Possibly related", to AAV-hAADC-2 in this cohort, the study moves to high dose cohort.

At the time of 6 months after the infusion, investigator assesses the treatment effect of AAV-hAADC-2 on the basis of subject diaries, clinical assessment and levodopa requirement dosage. At the same time, investigator assesses a relationship between the dose of AAV-hAADC-2 infused and the amount of intra-putaminal expression by FMT-PET imaging.

The investigator also assesses the safety for 5 years after the baseline examination. Long-term follow up study is additionally conducted for 10 years in reference to guideline of FDA.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 6 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I /II Study of Intra-putaminal Infusion of Adeno-Associated Virus Encoding Human Aromatic L-Amino Acid Decarboxylase in Subjects With Parkinson's Disease
Study Start Date : April 2015
Estimated Primary Completion Date : October 2018
Estimated Study Completion Date : January 2022

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Cohort1
The target putamen for AAV-hAADC-2 infusion is identified on MRI image that has been taken prior to the operation, and then subjects will be bilaterally infused with a total volume of 200 µL at a total of 4 sites (2 sites in left putamen, 2 sites in right putamen; 50 µL per site) at a flow rate of 3 µL per minute.
Genetic: Cohort1
AAV-hAADC-2 is administered via bilateral intra-putaminal infusion. The number of vector genomes (vg) administered in this cohort is 3x10^11 vg/subject.

Experimental: Cohort2
The target putamen for AAV-hAADC-2 infusion is identified on MRI image that has been taken prior to the operation, and then subjects will be bilaterally infused with a total volume of 600 µL at a total of 4 sites (2 sites in left putamen, 2 sites in right putamen; 150 µL per site) at a flow rate of 3 µL per minute.
Genetic: Cohort2
AAV-hAADC-2 is administered via bilateral intra-putaminal infusion. The number of vector genomes (vg) administered in this cohort is 9x10^11 vg/subject.




Primary Outcome Measures :
  1. The safety of intra-putaminal infusion of AAV-hAADC-2 as measured by adverse events (including Abnormal laboratory test results) with Classification criteria for severity of adverse reactions (dated 29th Jun,1992). [ Time Frame: 6 months ]
    Confirm the adverse events (including Abnormal laboratory test results) with Classification criteria for severity of adverse reactions (dated 29th Jun,1992).


Secondary Outcome Measures :
  1. The treatment effect of intra-putaminal infusion of AAV-hAADC-2 [ Time Frame: 6 months ]
    Assess the improvement of Parkinson's symptom as recorded in the subject diaries, clinical assessment and requirement dosage of levodopa.

  2. The amount of intra-putaminal expression of AAV-hAADC-2 [ Time Frame: 6 months ]
    Assesses a relationship between the dose of AAV-hAADC-2 infused and the amount of intra-putaminal expression by FMT-PET imaging.



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Ages Eligible for Study:   35 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Patients with idiopathic Parkinson's disease meet diagnostic criteria for Specified Disease designated by the Ministry of Health, Labour and Welfare (1995) : the Research Committee of CNS Degenerative Disease, L-Dopa is effective in the early disease stage and no findings suggestive of CNS Degenerative Disease are found.
  2. Age ≤ 75 years at the time of medical treatment.
  3. Age at onset ≥ 35 years.
  4. Duration of L-dopa therapy ≥ 5 years.
  5. Hoehn and Yahr Stage IV in OFF state at the onset of medical treatment.
  6. Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Scale Part III (MDS-UPDRS-III), minimum motor score of 30 to a maximum motor score of 100 in OFF state.
  7. Positive response to dopaminergic therapy as evidenced by remarkable improvement in MDS-UPDRS-III motor score between the defined "OFF" and "ON" state: a minimum 16 points improvement in the MDS-UPDRS-III after dopaminergic therapy.
  8. Patients who can undergo the stereotaxic surgery for Parkinson's disease due to the intolerable motor complication minimum score of 4 to a maximum score of 9 in the MDS-UPDRS-IV part B (diurnal fluctuation of symptom) , not responsive to optimal medical therapy.
  9. To be able to comply with the requirements, including the frequent clinical examination after medical treatment, in this study.
  10. To keep the therapeutic medicine for Parkinson's disease for at least 2 months prior to participation in this study.
  11. Written informed consent.

Exclusion Criteria:

  1. Patients who is suspected secondary / atypical parkinsonism based on the medical history of cerebral vascular disease, exposure to antipsychotic or toxic agents, and encephalitis or based on the symptom of Progressive supranuclear palsy, Pyramidal tract sign, autonomic sign, Dementia, Hallucination, Delusion and so on or based on the finding by magnetic resonance imaging (MRI) such as Lacunar infarct or atrophy of the midbrain tectum and atrophy of the pons and the cerebellum.
  2. Patients with history of 3 hours or more of intensive or violent dyskinesias in the past 6 months.
  3. Patients with previous the stereotaxy for Parkinson's disease (pallidotomy, thalamotomy, deep brain stimulation) .
  4. Mini-Mental State Examination (MMSE) ≤ 20 or patient with a diagnosis of dementia in the neuropsychological evaluation.
  5. Patients with medical history of Hallucination, Delusion, schizophrenia or affective disorder within 6 months of informed consent.
  6. Patients with history of significant cardiovascular disease including cerebrovascular accident.
  7. Malignant neoplasm in the brain, clinically significant neurological disease (for example significant brain atrophy not consistent with age).
  8. History of other malignancy, with the exception of treated carcinoma cutaneum, within 5 years.
  9. Uncontrolled hypertension: systolic blood pressure ≥ 160 mmHg.
  10. Coagulopathy or need for anticoagulant therapy.
  11. Clinically significant immune dysfunction (for example, the case who require the use of immunosuppressive drugs).
  12. Geriatric Depression Scale (GDS) short scale ≥ 10 points, or if on antidepressant, the score > 5 points.
  13. On monoamine oxidase (MAO)-A inhibitors, or antipsychotic medications.
  14. Unable to scan MRI.
  15. Cases without abnormal finding in FMT-PET.
  16. Premenopausal female or male who desire impregnating a female (excluded: in case when sperm is cryopreserved prior to gene therapy and child is born by using the sperm).
  17. Past medical history of convulsive seizure within 3 years or receiving antiepileptic drug or patients with epileptic aberrance in the electroencephalography.
  18. Past medical history of serious drug allergy.
  19. Patients who have participated in other clinical trial within 6 months.
  20. Patients who meet any of the following criteria:

    1. Serious renal disorder ( Cr ≥ 2.0 mg/dl and BUN ≥ 25mg/dl)
    2. Serious hepatic disorder ( AST (GOT) / ALT (GPT) ≤2.5xupper limit of normal (ULN)
    3. Serious diabetes (casual blood glucose or fasting blood glucose ≥ 200 mg/dl and HbA1c ≥ 9 %)
  21. Any other patients judged by investigators to be inappropriate for the subject of this study.

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): NCT02418598


Contacts
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Contact: Shin-ichi Muramatsu, MD, PhD +81-285-58-7543 muramatsu@jichi.ac.jp
Contact: Yoshihito Ando, MD +81-285-58-7543 yacht-po@jichi.ac.jp

Locations
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Japan
Jichi Medical University Recruiting
Shimotsuke, Tochigi, Japan, 3290498
Contact: Shinichi Muramatsu, MD, PhD    +81-285-58-7543    muramats@jichi.ac.jp   
Contact: Yoshihito Ando, MD    +81-285-58-7543    yacht-po@jichi.ac.jp   
Sponsors and Collaborators
Jichi Medical University
Takara Bio Inc.
Gene Therapy Research Institution,Co.,Ltd.
Investigators
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Study Chair: Shin-ichi Muramatsu, MD, PhD Division of Oriental Medicine, Center for Community Medicine, Jichi Medical University; Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University; Division of Neurology, Department of Medicine, Jichi Medical University

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Responsible Party: Shinichi Muramatsu, Professor, Jichi Medical University
ClinicalTrials.gov Identifier: NCT02418598     History of Changes
Other Study ID Numbers: JMU-AAV-AADC-PD
First Posted: April 16, 2015    Key Record Dates
Last Update Posted: February 28, 2018
Last Verified: February 2018

Keywords provided by Shinichi Muramatsu, Jichi Medical University:
Adeno-associated virus
Aromatic L-amino acid decarboxylase
AAV-hAADC-2
AAV-2
Gene Therapy
Gene Transfer
Parkinson Disease
Basal Ganglia Disease
Brain Disease

Additional relevant MeSH terms:
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Parkinson Disease
Parkinsonian Disorders
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Dopa Decarboxylase
Antiparkinson Agents
Anti-Dyskinesia Agents