Precise Transplantation of hAESCs Into the Ventricle for Parkinson's Disease.

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of multiple treatments of hAESCs treatments, while exploring the effectiveness of hAESCs treatments for PD.

Detailed Description
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The study plans to use randomized controlled trial and recruit 12 participants with Idiopathic Parkinson's disease. The trial will be divided into two groups, hAESCs treatment group and control group, each group 6 subjects. Through surgical robot technology, hAESCs will be precisely multiple transplanted into the lateral ventricles, that is two times consolidation hAESCs treatments or placebo were added to the four times basic hAESCs treatments. Therapeutic safety and effectiveness of multiple treatments of hAESCs on PD will be evaluated to further develop the optimal stem cell treatment strategy.

Official Title
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The Precise Transplantation of Human Amniotic Epithelial Stem Cells Into the Ventricle Through Surgical Robot in the Treatment of Parkinson's Disease.

Conditions
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Parkinson's Disease

Intervention / Treatment
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* Biological: hAESCs treatment
* Biological: placebo (saline)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 30-70 years old, with more than 5 years primary Parkinson's disease history, male or female; The off-age UPDRS exercise score is between 38 and 70 points, two times before the operation, the down period UPDRS exercise score was stable, that is, (high value - low value) / high value ≤ 10%; The Parkinson treatment is stable for more than 3 months; Levodopa treatment was effective; No general anesthesia contraindications, no contraindications to stereotactic surgery and other conditions that interfere with clinical evaluation; No abnormalities affecting cell transplantation were found through the cranial MRI; Patients shall be properly cared during treatment, and caregivers can provide transplantation situations and assistance to the researcher if necessary. Exclusion Criteria: Atypical Parkinson's disease, such as Parkinson's syndrome, secondary Parkinson's disease; Only having tremor syndrome; off period or on period has serious movement disorders and cannot complete any routine exercise tasks; Symptoms of severe neurological deficits caused by other diseases; Severe mental symptoms or dementia; Patients are unwilling to cooperate or incapable of completing self-evaluation, and cannot complete the evaluator with the help of a doctor; History of striatum or extrapyramidal surgery, including deep brain stimulation (DBS); Injecting apomorphine treatment; Abnormal blood coagulation or ongoing anticoagulation therapy; Women of childbearing age who do not take effective contraception; Pregnant or lactation; Patients who have participated in other clinical studies of drugs or medical devices within 3 months; Botox toxin, phenol, subarachnoid injection of baclofen or interventional therapy for the treatment of dystonia or spasticity within 6 months; History of seizures or prophylactic anti-epileptic drugs; Alcohol or drug abuse; Severe cognitive impairment, depression, or behavioral disorder, defined as the Mini-Mental State Assessment Scale (MMSE) of less than 26 points, and the Hamilton Depression Rating Scale (HAMD) of greater than 35 points; Malignant tumor or active infection within 5 years; Serum virology showed positive results for hepatitis C virus (HCV) , treponema pallidum (TP) or HIV; Active hepatitis B (hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb) positive, and peripheral blood HBV DNA titer ≥1×10^3 IU/ mL); Abnormal liver and kidney function tests in the laboratory, liver and kidney function is defined as Alanine aminotransferase（ALT), Aspartate aminotransferase（AST) is less than 2.5 times the upper limit of normal, blood urea nitrogen (BUN) and Creatinine（Cr) are less than the upper limit of normal. Other conditions considered ineligible for inclusion by the investigator.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The study plans to recruit 12 patients who meet the criteria. 50 millions hAESCs will be transplanted to participants with PD.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: hAESCs treatment<br>A total of 6 times hAESCs transplants will be performed. 50 million (in 2ml) hAESCs will be transplanted into the ventricle of participants through the Ommaya sac (set as day 0 at the beginning of the trial). Subsequently, hAESCs ventricle transplants will be performed at 1 month ±5 days, 2 months ±5 days, 3 months ±5 days, 6 months ±5 days, and 9 months ±5 days after the first cell transplantation, with a volume of 50 million cells (in 2 ml) each time. | Biological: hAESCs treatment<br>* Precise Transplantation of hAESCs Into the Ventricle for Parkinson's Disease.<br>|
| Placebo Comparator: Control group<br>Four times hAESCs transplants and two times placebo (cell preservation solution) injections will be performed by Ommaya sac. 50 million (in 2ml) hAESCs will be transplanted into the ventricle of participants (set as day 0 at the beginning of the trial). Subsequently, hAESCs will be transplanted into the ventricle for 3 times, respectively, at 1 month ±5 days , 2 months±5 days , and 3 months ±5 days after the first cell transplantation, with a volume of 50 million cells (in 2 ml) each time. Ventricle injection of 2 ml placebo (cell preservation solution) will be performed at 6 months ±5 days and 9 months ±5 days after the first cell transplantation. | Biological: placebo (saline)<br>* 2 times placebo (normal saline) injections as control group<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with adverse event (AE), serious adverse event(SAE) and adverse events of special interest(AESI) | AE occurring throughout the study period will be evaluated using the CTCAE V5.0 standard. AE/SAE and AESI were evaluated after Ommaya sac installation by laboratory examination, measurement of vital signs, physical examination, and subjects' symptoms to detect new abnormalities and/or deterioration of previous conditions and evaluate the safety of the study. AESI is defined as intracranial infection, hemorrhage, rejection, and edema within 7 days after Ommaya sac installation, as well as acute allergic reactions and ectopic mass formation associated with study therapy. | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Unified Parkinson's Disease Rating Scale (UPDRS) in OFF state between the experimental group and the control group at 12 months after the first hAESCs treatment | UPDRS is used for evaluating the impairment and disability associated with Parkinson's Disease (PD). It consists of four sections: (1) Mentation, behavior, and mood; (2) Activities of daily living (ADLs); (3) Motor; and (4) Complications. The UPDRS score ranges from 0 to 199, with higher score indicating greater disability | day 0, 1 month, 2 month, 3 month, 6 month, 9 month and 12 month. | 
| Changes in the Hoehn and Yahr scale | Hoehn and Yahr scale is used to provide a general estimate of clinical function of PD patients, combining functional deficits (disability) and objective signs (impairment). The Hoehn and Yahr score ranges from 0 to 5, with higher score indicating higher dysfunction of PD patients. | day 0, 1 month, 2 month, 3 month, 6 month, 9 month and 12 month. | 
| Changes in the Schwab and England score | The Schwab and England score develop a scale that describes the capacity of daily living shown by a PD patients. It measures the following three areas: dependence, abilities, and awareness. The Schwab and England score range from o% to 100%, with higher scores indicating greater healthy status. | day 0, 1 month, 2 month, 3 month, 6 month, 9 month and 12 month. | 
| Changes in the Parkinson's Disease Questionnaire (PDQ-39) | PDQ-39 provides the evidence of the quality of life of a PD patient. The higher the score, the lower the quality of life of PD patients. | day 0, 1 month, 2 month, 3 month, 6 month, 9 month and 12 month. | 
| Changes in the Hamilton Depression (HAMD) Scale | HAMD is the most widely used scale in clinical evaluation of depression in PD patients. This project takes 8 points as the critical value of depression, and the total score over 35 points is considered as severe depression, more than 20 points is likely to be diagnosed with depression, less than 8 points is not depressed. | day 0, 1 month, 2 month, 3 month, 6 month, 9 month and 12 month. | 
| Differences in biochemical indicators of cerebrospinal fluid | Cerebrospinal fluid indicator tests include biochemical indicators and the following parameters: Dopamine (DA), high vanillic acid (HVA), 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), norepinephrine (MHPG), α synuclein (α-synuclein), amyloid deposition (Aβ42), Tau protein (Tau) Protein, Neurofilament light (NF-L), and yKL-40 (YKL-40). | day 0, 1 month, 2 month, 3 month, 6 month, 9 month and 12 month. | 
| Cranial dopamin transporter measured by positron emission tomography (PET)- magnetic resonance imaging (MRI) | Changes of cranial expression of dopamine transporter investigated by PET-MR | 4 month, 6 month, 12 month | 
| Glucose metabolism measured by 18F-Fluoro-2-deoxy-glucose (FDG) PET scan | Changes of cranial glucose metabolism investigated by PET-MR | 4 month, 6 month, 12 month | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Parkinson's Disease; stem cell