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Kyoto Trial to Evaluate the Safety and Efficacy of iPSC-derived dopaminergic progenitors in the treatment of Parkinson's Disease (Kyoto Trial to Evaluate the Safety and Efficacy of iPSC-derived dopaminergic progenitors in the treatment of Parkinson's Disease)

Kyoto Trial to Evaluate the Safety and Efficacy of iPSC-derived dopaminergic progenitors in the treatment of Parkinson's Disease

Ryosuke Takahashi

Kyoto University Hospital

54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507

neuroofc@kuhp.kyoto-u.ac.jp

Nobukatsu Sawamoto

Kyoto University Hospital

54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507

+81-75-751-3771

neuroofc@kuhp.kyoto-u.ac.jp

COMPLETED

Sept. 25, 2018

Interventional

single group, non-control, open label

open(masking not used)

No

1-2

1)The patient has a diagnosis of PD (clinically established or clinically probable) in accordance with the MDS Clinical Diagnostic Criteria for Parkinson's Disease (2015).
2)The patient plans to undergo transplantation of human iPSC-derived dopaminergic progenitors.
3)The patient has a poor response to existing drug treatments.
4)The patient is >= 50 years and < 70 years of age at the time of informed consent.
5)The patient has had PD for at least 5 years.
6)The patient has both ON and OFF (as demonstrated by the MDS-UPDRS Part III and a symptom diary).
7)The patient is in stage 3 or higher on the Hoehn and Yahr scale at OFF time.
8)The patient is in stage 3 or lower on the Hoehn and Yahr scale at ON time.
9)The patient has an L-dopa response of 30% or more without influence of antiparkinsonian drugs.
10)The patient has a decrease pattern characteristic to PD in the basal ganglia region on DAT scan.
11)The patient has the following organ functions as determined by laboratory tests within 7 days before registration:
i)Neutrophil count >= 2,000/microL
ii)Platelet count >= 5.0 X 10^4/microL
iii)AST, ALT =< 3.0 X upper limit of normal at the study site
iv)Total bilirubin =< 1.5 X upper limit of normal at the study site
v)eGFR >= 60 mL/min/1.73 m2
vi)eGFR (mL/min/1.73 m2) = 194 X Cr^-1.094 X age^-0.287 (X 0.739 for females)
12)The patient provides written informed consent to participate in the study.
A patient who cannot write due to the disease may be enrolled if he or she provides verbal consent and a witness signs the informed consent form.

1)The patient has a symptomatic organic lesion as detected by head MRI.
2)The patient has abnormal immune function.
3)The patient is demented or deemed at high risk of dementia.
4)The patient has bleeding tendency or abnormal coagulation function.
5)The patient is HBs antigen-positive, or HBs antibody- or HBc antibody-positive with evidence of HBV-DNA.
6)The patient is anti-HIV antibody-positive.
7)The patient is anti-HTLV-1 antibody-positive.
8)The patient has active infection such as hepatitis C or syphilis (STS/TPHA).
9)The patient has contraindication to the study drug (tacrolimus), concomitant drugs (e.g., levodopa, carbidopa, MRI contrast), and/or their components.
10)The patient has hypersensitivity to the study drug (tacrolimus), concomitant drugs (e.g., levodopa, carbidopa, MRI contrast), and/or their components.
11)The patient has severe allergic to gentamicin, a bovine-derived ingredient l or a pig-derived ingredient.
12)The patient has undergone transplantation of human iPSC-derived dopaminergic progenitors.
13)The patient has any of the following diseases concurrently:
.Malignant neoplasm
.Epilepsy
.Mental disease (e.g., depression, bipolar disorder, schizophrenia)
.Other serious concurrent diseases (e.g., cerebrovascular disorder, heart disease, chronic respiratory disease, inadequately controlled hypertension, diabetes mellitus)
14)The patient has a history of any of the following:
.Malignant neoplasm
.Epilepsy
.Cerebral hemorrhage
.Mental disease (e.g., depression, bipolar disorder, schizophrenia)
.Pallidotomy, thalamotomy, or deep brain stimulation
15)The patient is pregnant or lactating, or does not agree to avoid pregnancy throughout the study.
16)The patient, in the opinion of the investigator or subinvestigator, is not appropriate to conduct the study safely.

Both

Parkinson's disease

Intervention type: Name of intervention:cell transplantation Dose form / Japanese Medical Device Nomenclature:OTHER Route of administration / Site of application:Intrastriatal Dose per administration:2.4 X 10^6 cells(for the first 3 patients),4.2-5.4X10^6 cells(for the 4th and later patients) cells Dosing frequency / Frequency of use:ONCE Planned duration of intervention:Single dose, N/A Intended dose regimen:Under general anesthesia using a stereotactic brain surgery system, human iPSC-derived dopaminergic progenitors will be transplanted into the bilateral putamen. For the first 3 patients, approximately 2.4X10^6 cells will be delivered at each side. For the 4th and later patients, 4.2-5.4X10^6 cells will be transplanted at each side. detailes of teratment arms:Immunosuppressant treatment will be started in the morning on the day of transplantation, continued until 52 weeks after transplantation, and then tapered off to zero over 12 weeks. In the early phase, the immunosuppressant is orally administered 0.03 to 0.15 mg/kg, twice a day, and the targeted blood concentration is within a range of 5-10 ng/mL as a trough value.

Parkinson's disease

cell transplantation

D010300

D017690

1) Incidence and severity of adverse events 2) Presence or absence of graft expansion in the brain at 24 months after transplantation

<Safety endpoints>
1) Uptake of [18F]FLT
2) Uptake of [18F]GE180
3) Dyskinesia score
4) Graft size (MRI)

<Efficacy endpoints>
1) MDS-UPDRS Part III total score (at ON and OFF times)
2) MDS-UPDRS Part II total score
3) MDS-UPDRS Part I total score
4) Sum score of MDS-UPDRS Part I, Part II, and Part III (at ON and OFF times)
5) Average daily ON duration (with or without dyskinesia) and OFF duration
6) Bradykinesia subscale
7) Uptake of [18F]FDOPA
8) Uptake on DAT scan
9) Parkinson's Disease Questionnaire (PDQ-39)
10) Hoehn and Yahr severity
11) L-dopa equivalent dose
12) Euro-QOL 5 Dimensions-5 Levels (EQ-5D-5L)
13) Work Productivity and Activity Impairment Questionnaire (WPAI)
14) Nursing care category

May. 08, 2018