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RESEARCH ARTICLE
Asia Pac J Clin Trials Nerv Syst Dis 2018,  3:81

Transplantation of autologous neural stem cells for treatment of Parkinson's disease: study protocol for a non-randomized controlled trial


Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, China

Date of Web Publication15-May-2018

Correspondence Address:
De-Qin Geng
Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3932.232081

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  Abstract 

Background and objectives: As degenerative changes in dopaminergic neurons occur only in the substantia nigra and striatum of patients with Parkinson's disease (PD), cellular therapy is suitable for this condition. However, previous clinical studies using stem cells for treatment of PD have short follow-ups. Thus, studies with longer follow-ups are required to further investigate the efficacy of stem cell-based therapy.
Design: A non-randomized controlled trial.
Methods: Ninety eligible PD patients will be recruited from the Department of Neurology at the Affiliated Hospital of Xuzhou Medical University, China. These patients will be assigned to three groups according to each patient's or their legal guardians’ wishes (n = 30 per group). In the control group, 12-week routine drug treatment will be performed. In intrathecal administration and intravenous administration groups, intrathecal administration of autologous neural stem cells (NSCs) into the subarachnoid space or intravenous administration of autologous NSCs will be performed once a week for 4 successive weeks in addition to the 12-week routine drug treatment.
Outcome measures: The primary outcome measure is symptom improvement rate at 36 months post-treatment. Secondary outcome measures are nigrostriatal dopamine content, α-synuclein content in blood and cerebrospinal fluid, Barthel index, and safety indicators.
Discussion: This study will be performed to demonstrate efficacy of autologous NSC transplantation as a prospective treatment for PD and investigate differences between intrathecal and intravenous transplantation routes, thus providing objective quantitative evidence for clinical applications.
Ethics and dissemination: This study was designed in July 2017. Ethics approval from Medical Ethics Committee of the Affiliated Hospital of Xuzhou Medical University of China was achieved on December 22, 2017 (approval No. XYFY2017-KL052-01). The study protocol was registered on December 25, 2017. Patient recruitment began in January 2018 and will end in January 2019. Each patient will be followed up for 36 months. Follow-ups will be completed in January 2022. Data analysis will be performed in July 2022. Results will be disseminated by publication in a peer-reviewed journal.
Trial registration: This trial was registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-ONC-17014141). Protocol version (1.0).

Keywords: Parkinson′s disease; autologous neural stem cells; subarachnoid transplantation; intravenous transplantation; Hoehn and Yahr scale; The Unified Parkinson′s Disease Rating Scale; non-randomized controlled trial


How to cite this article:
Ding HM, Wang XL, Mu YF, Li JM, Geng DQ, Xu T, Wan MR, Liu XY. Transplantation of autologous neural stem cells for treatment of Parkinson's disease: study protocol for a non-randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:81-8

How to cite this URL:
Ding HM, Wang XL, Mu YF, Li JM, Geng DQ, Xu T, Wan MR, Liu XY. Transplantation of autologous neural stem cells for treatment of Parkinson's disease: study protocol for a non-randomized controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2021 May 12];3:81-8. Available from: https://www.actnjournal.com/text.asp?2018/3/2/81/232081


  Introduction Top


Research background

With an aging population, increasing attention has been paid to geriatric diseases. Parkinson's disease (PD) is the second most common degenerative disease of the central nervous system in middle-aged and elderly people. It is mainly characterized by degeneration of nigrostriatal dopaminergic neurons and the formation of Lewy bodies, leading to decreased nigrostriatal dopamine transmission and disruption of the balance between dopamine and acetylcholine, which results in motor symptoms such as static tremor, myotonia, bradykinesia, and postural balance disorders, and non-motor symptoms, such as hyposmia, constipation, and abnormal sleep behaviors (Poewe, 2008; Kalia and Lang, 2015; Sveinbjornsdottir, 2016). According to an epidemiological study (Zou et al., 2015), Chinese patients with PD account for half of PD patients worldwide. The incidence of PD in Chinese people aged over 65 years is 16,440.3/100,000, and the incidence increases with age. There are many treatment options available for PD, including medication, surgery, cell and tissue transplantation, and gene therapy, although medication is primarily used in the clinic (Connolly and Lang, 2014). However, current drugs for treating PD can only improve symptoms but cannot delay disease progression. Moreover, with the prolongation of patient's medication time, the efficacy of drugs is substantially reduced, such that motor symptoms cannot be completely alleviated in the majority of patients with late-stage PD. In addition, combining many drugs for treating PD can cause an assortment of complications, including “switching” and “fluctuating” phenomena, which greatly influence patient's quality of life (Zhang and Tan, 2016).

Although the etiological mechanism of PD is presently unknown, the site of lesions is clear, i.e., the substantia nigra and the striatum. That is to say, degenerative changes in dopaminergic neurons only occur in these two sites (Davie, 2008). Therefore, cell transplantation is very suitable for treatment of PD. In previous studies, we found that stem cell transplantation can effectively improve the symptoms of PD patients and reverse the progression of PD (Ren et al., 2014). Therefore, stem cell transplantation is considered the most promising and potential treatment option for PD [Table 1].
Table 1: Previous preclinical and clinical studies of stem cell transplantation for Parkinson's disease

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Features and objective of this study

Our team previously found that transplantation of autologous neural stem cells (NSCs) differentiated from autologous bone marrow mesenchymal stem cells (BMSCs) can effectively improve clinical symptoms, vital signs, and the quality-of-life of patients with degenerative diseases of the central nervous system; moreover, the treatment is safe (Ren et al., 2014). However, in our previous study, the sample size was small and the follow-up time was short. Therefore, it is necessary to perform a study involving a larger number of patients to further confirm the efficacy of transplantation of autologous NSCs differentiated from autologous BMSCs in the treatment of PD, and to investigate the long-term safety of this treatment method through prolonged follow-up time. At present, intrathecal administration and intravenous administration are available for cell transplantation in a clinical setting. However, whether these two administration routes of autologous NSCs differ with regard to efficacy for treatment of PD remains unclear. In this study, we investigated the efficacy of transplantation of autologous NSCs differentiated from autologous BMSCs in the treatment of PD by evaluating symptom improvement rate, nigrostriatal dopamine content, α-synuclein content in blood and cerebrospinal fluid, Barthel index, and safety indicators. We also compared differences in efficacy between intrathecal and intravenous administration routes of NSCs.


  Methods/Design Top


Study design

Thirty eligible PD patients will be recruited from the Department of Neurology at the Affiliated Hospital of Xuzhou Medical University, China. These patients will be assigned to three groups according to each patient's or their legal guardians’ wishes (n = 30 per group). In the control group, 12-week routine drug treatment will be performed. In intrathecal administration and intravenous administration groups, intrathecal administration of autologous neural stem cells (NSCs) into the subarachnoid space or intravenous administration of autologous NSCs will be performed once a week for 4 successive weeks in addition to 12-week routine drug treatment. The primary outcome measure is symptom improvement rate at 36 months post-treatment. Secondary outcome measures are nigrostriatal dopamine content, α-synuclein content in blood and cerebrospinal fluid, Barthel index, and safety indicators.

Recruitment

Recruitment will be performed through posters on a bulletin board that is used to advertise for patients in the Department of Neurology at the Affiliated Hospital of Xuzhou Medical University, China. After being informed of the trial objective and procedure, patients interested in participation or their close relatives will contact the project manager through telephone, e-mail, or Wechat.

Population selection

Inclusion criteria

Patients who receive treatment in the Department of Neurology at the Affiliated Hospital of Xuzhou Medical University and meet all of the following criteria will be considered for inclusion:

  • Patients with PD diagnosed according to Chinese Parkinson's Disease Treatment Guidelines (CPDTG; Chinese Medical Association Chinese Society of Neurology Parkinson's Disease and Dyskinesia Team and Chinese Medical Doctor Association Chinese Congress of Neurological Physicians Parkinson's Disease and Dyskinesia Team, 2016);
  • Normal hematopoietic function, no bleeding tendency, and normal routine blood indicators: hemoglobin (HGB) ≥ 90 g/L, white blood cells 4.0 × 109/L, neutrophils ≥ 1.5 × 109/L, platelets ≥ 100 × 109/L;
  • Liver function: total bilirubin ≤ 1.5 times the upper limit of normal; aspartate transaminase and alanine aminotransferase ≤ 1.5 times the upper limit of normal; alkaline phosphatase ≤ 1.5 times the upper limit of normal;
  • Kidney function: Blood urea nitrogen and serum creatinine ≤ 1.5 times the upper limit of normal, creatinine clearance ≥ 80 mL/min;
  • No lung infection as confirmed by chest CT;
  • No other severe heart, liver or kidney diseases;
  • No severe viral or bacterial infection;
  • Age at 40–80 years, of either gender;
  • Provision of informed consent by patient or their guardian.


Exclusion criteria

Patients who meet one or more of the following conditions will be excluded from this study:

  • Patients who are highly allergic or have a history of severe allergies;
  • Inability to cooperate with treatment or efficacy evaluation because of psychiatric symptoms or mental disorder;
  • A need for anti-infective therapy because of systemic infections or severe local infections;
  • Concomitant dysfunction of important organs such as the heart, lung, brain, kidney or liver;
  • Coagulation disorders (such as hemophilia);
  • Infectious diseases;
  • Severe autoimmune diseases;
  • Upon the request of the sponsor for safety reasons;
  • Use of other clinical drugs within 3 months prior to screening;
  • Pregnant woman.


Withdrawal criteria

Patients meeting one or more of the following conditions will be withdrawn from this study. The case withdrawal reasons should be reported and recorded in the case report form (CRF). Withdrawn patients will not be included in the final analysis.

  • Presence of severe adverse events;
  • Loss to follow-up;
  • Low-quality patient's BMSCs;
  • No treatment or no records after treatment;
  • Inability to evaluate curative effects because of a combined use of other therapies or drugs to enhance therapeutic efficacy.


Grouping and blinding

Grouping will be performed according to each patient's or their legal guardians’ wishes.

Interventions

  • Control group: According to the Chinese Parkinson's Disease Treatment Guidelines (3rd edition), the control group will be administered one or more drugs. According to the severity of clinical symptoms, the progression of the disease can be divided into mild (Hoehn and Yahr Scale Stages 1–2.5) and moderate to severe (Hoehn and Yahr Scale Stages 3–5). PD drugs currently available in China include (1) compound levodopa; (2) nonergodic dopamine receptor agonist; (3) monoamine oxidase B; (4) amantadine; (5) catechol-O-methyl transferase inhibitor; and (6) anticholinergic drugs, such as Benzeso.
  • - Drugs (1) + (2) or drugs (2) + (6) will be given to mild PD patients aged < 60 years who present with obvious tremor, while drugs (2) + (3) will be given to mild PD patients who present with unobvious tremor;

    - Drugs (1) + (2) will be given to mild PD patients aged ≥ 60 years who present with obvious tremor, while drugs (1) + (3) will be given to mild PD patients who present with unobvious tremor;

    - Drug (4) will be given to mild PD patients of any age but with cognitive disorder;

    - Drugs (1) + (2) + (3) will be given to moderate to severe PD patients of any age;

    - Drug (6) will be added for moderate to severe PD patients aged < 60 years presenting with tremor

    - Drug (4) will be added for moderate to severe PD patients with cognitive disorder [Figure 1].
    Figure 1: Drug treatment for Parkinson's disease.
    Note: (1): Compound levodopa; (2): nonergodic dopamine receptor agonist; (3): monoamine oxidase B inhibitor; (6) anticholinergic drug


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  • Intrathecal administration group: within 1 week prior to treatment, BMSCs will be collected for in vitro culture.
  • - BMSC isolation and culture: under sterile conditions, 20 mL of autologous bone marrow will be collected using a routine method. After heparin anticoagulation, 20 mL of bone marrow will be mixed with an equal amount of phosphate-buffered saline (PBS). Subsequently, the mixture will be centrifuged at 3500 rpm for 15 minutes. Adipose and supernatant will be discarded. Cells will be re-suspended in PBS. After addition of an equal amount of Ficoll the resulting mixture will be centrifuged at 2500 rpm for 15 minutes. After three washes with PBS and one wash with 2–5% human autologous low-glucose DMEM/F12, mononuclear cells will be inoculated into a 25 cm2 flask in a humidified incubator at 37°C saturated with 5% CO2. Cells at this time will be recorded as passage 0 (P0). Half the amount of medium will be refreshed at 3 days. Thereafter, the whole amount of medium will be refreshed every 5 days. When cells reach 80–100% confluency, adherent cells will be digested with a mixture of 0.125% trypsin and 0.02% EDTA and passaged at 1:3 until they approach confluency. The above procedure will be repeated for cell passage and amplification. Passages 1–5 will be harvested.

    - Induced neuron-like cell differentiation of BMSCs by cerebrospinal fluid: cerebrospinal fluid will be harvested by lumbar puncture. P3 BMSCs (4.0 × 104/mL) will be seeded into a poly-L-lysine–treated 6-well plate. When cells reach 80% confluency, they will be cultured in MesenCult culture medium containing 10 μL of cerebrospinal fluid. Cells will be identified by inverted microscopy, electron microscopy, flow cytometry, immunohistochemical staining, fluorescent immunohistochemistry assay, and reverse transcription-polymerase chain reaction. The time taken to generate a clinically desired amount of NSCs (1 × 107/mL) and the precise number of NSCs harvested will be recorded. Based on the use of PD drugs, autologous NSCs (2 × 107) will be intrathecally injected into the subarachnoid space once a week for 4 successive weeks.

  • Intravenous administration group: within 1 week prior to treatment, BMSCs will be collected and in vitro cultured. Based on the use of PD drugs, autologous NSCs (2 × 107) will be intravenously (via superficial veins in the limb extremity, such as dorsal venous rete of hand and median cubital vein) into the body once a day for 4 successive days.


Outcome measures

Primary outcome measure

  • Symptom improvement rate at 36 months post-treatment: evaluated by comparing the Hoehn and Yahr Scale stage and Unified Parkinson's Disease Rating Scale (UPDRS) scores between 36 months post-treatment and prior to treatment. The Hoehn and Yahr Scale is a clinical rating scale that includes six rating stages (ranging from 0–5), with higher stages indicating more severe PD symptoms (Goetz et al., 2004). The UPDRS scoring system is widely used for the clinical evaluation of PD, with higher scores indicating more severe PD symptoms. Lower Hoehn and Yahr scale stage and UPDRS score represent more obviously improved PD symptoms, that is, increased symptom improvement rate.


Secondary outcome measures

Secondary outcome measures will be evaluated prior to and at 1, 3, 6, 9, 12, 18, 24, 30, and 36 months after treatment.

  • Symptom improvement rate at 1, 3, 6, 9, 12, 18, 24, 30, and 36 months after treatment;
  • Nigrostriatal dopamine content: nigrostriatal dopamine transporter content will be determined and nigrostriatal dopamine content will be indirectly calculated;
  • α-Synuclein content: α-synuclein content in blood and cerebrospinal fluid will be determined using an enzyme-linked immunosorbent assay;
  • Barthel index: used to measure patient performance in activities of daily living before and after treatment. A score of 100 indicates excellent performance in activities of daily living, while 0 indicates poor performance and no independent ability (Mahoney and Barthel, 1965);
  • Safety indicators: Vital signs, physical examination, laboratory and imaging examinations, including routine blood and urine tests, liver function, renal function, electrocardiogram, and chest CT.


Adverse events

Adverse events refer to adverse medical event that occurs after a subject receives a test drug or cellular therapy, which may or may not necessarily have a causal relationship with the test drug or cellular therapy. During the clinical trial, changes in clinical symptoms, vital signs, and laboratory examinations will be evaluated. Any exacerbation of an existing condition or illness will be considered an adverse event.

Studies have shown that transient fever and chills generally occur after treatment with autologous NSCs. However, most fever patients have a body temperature of < 39°C and this symptom disappears after physical cooling. A skin rash can disappear after conventional antiallergic treatment. Headache, dizziness, or pain in puncture site can relieve itself.

Adverse reactions occurring during the clinical trial can be rated as mild, moderate, severe, or life threatening. A mild adverse reaction will cause a patient slight discomfort, an affected daily life, and the need for clinical management. A moderate adverse reaction occurs when a patient actively narrates that his/her daily life has been affected, but that he/she can endure the suffering, and there is a need for clinical management. A severe adverse reaction occurs when a patient objectively expresses that he/she cannot tolerate the affected daily life, and he/she needs bed rest and emergent clinical management. All adverse events-related details (the nature, first onset time, severity, relationship with cellular therapy, duration, one-time or intermittent, and management method) will be recorded in the CRF. All non-severe adverse events that occur during the entire study period from subject recruitment to the end of follow-up will be recorded through regular telephone contact and/or visits, or spontaneous subject reports.

Severe adverse events are medical events that occur during the clinical trial that need hospitalization and/or prolongation of hospital stays, or lead to disability, affect work performance, threaten patient's life, or result in death or congenital deformity. Any severe adverse event that occurs during the treatment or observation stage, no matter its association with cellular therapy, will be reported to the partners, ethics committee, or relevant regulatory authorities within 24 hours after he/she discovers the incident. Researchers should not delay the reporting of severe adverse events to partners, ethics committees, and relevant regulatory authorities. The information contained in the initial report should include the following: subject's trial number (entry number), pinyin abbreviation code of the subject's name, time and date of the first cellular therapy, time and date of the adverse event, a brief description of the adverse event, countermeasures taken, and researchers’ opinions on the relationship between the event and cellular therapy. Severe adverse events will be reported in a timely manner to municipal, provincial, and state food and drug administrations. All severe and non-severe adverse events, no matter their association with the cellular therapy, must be monitored until the symptoms subside and related clinical laboratory parameters have returned to baseline, or until the observed changes are satisfactory, or until death occurs. In this case, if feasible, a pathology report will be reported. All results will be recorded in the CRF.

The corresponding treatment methods for adverse events are shown in [Table 2].
Table 2: Management of adverse events that occur after treatment with autologous neural stem cells

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Trial procedure

Flow chart of this study is shown in [Figure 2]. Timing of outcome assessment is shown in [Table 3].
Figure 2: Study flow chart.
Note: PD: Parkinson's disease.


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Table 3: Timing of primary and secondary outcome measures

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Sample size

In accordance with our previous experience, we hypothesized that the symptom improvement rate of the intrathecal administration and intravenous administration groups would be 75% and 50%, respectively. Assuming β = 0.2, significance level α = 0.05 (one-sided), a final effective sample size of n = 59 was calculated using the PASS11.0 software (PASS, Kaysville, UT, USA). Assuming a patient loss rate of 20%, we would require 71 patients per group. Thus, in total 273 patients will be included in this study. However, due to the limited funding for this trial, only 10 patients will be included in each group in the preliminary period, and thus there will be 30 patients in three groups.

Statistical analysis

Continuous variables will be expressed as number of cases, median, mean, standard deviation, and range. Categorical variables will be used as frequency, composition ratio, or percentage. Chi-square test or Fisher's exact probability method will be used for comparisons of categorical variables between groups. Independent-samples t-test or Wilcoxon rank sum test will be used for comparisons of the means of continuous variables between groups. A Signed Rank test will be used for evaluating variables in one group across different time points. A significance level of 0.05 will be designated for all two-sided statistical tests. Statistical analyses will be performed using SAS9.0 software (SAS Institute, Cary, NC, USA) according to the intention-to-treat principle.

Data collection and management

Each patient's CRF will be done in duplicate. It will be filled with a pen or a waterborne ink pen by the responsible physicians during the clinical observation and will not be arbitrarily altered. Areas that need to be corrected will be marked with a pen and correct data will be written. Then, the corrected areas will be dated and signed. All test reports should be attached to the CRF. The CRF must be signed by the responsible physicians and verified and signed by the principal researchers in the institute.

Statistical analysis will be performed according to the clinical trial protocol. Statistical analysis reports will be made by medical statisticians according to the bioassay technology guiding principle for clinical trials.

During the clinical trial, all original data (including laboratory test reports) will be preserved by the researchers. Duplicate CRFs (copies for clinical trial center) will be collected and sent to the trial sponsor. After a careful recheck of information recorded in CRFs, all copies for the clinical trial center will be collected for statistical analysis.

The original data will be preserved by clinical trial centers until 5 years after the termination of clinical trials. Original data includes CRFs, original hospital records, informed consents, and details of drug application.

A project monitor will regularly conduct on-site audits to ensure that the clinical trial program is being strictly compliant. The project monitor will recheck data records and ensure all data recorded in the CRF is identical to the original data.

All adverse events will be recorded in detail, properly handled, and tracked until they are resolved or the disease condition is stable.

All adverse events will be reported to the Ethics Committee and competent authorities in a timely manner, in accordance with regulations; the main investigators will regularly review all adverse events in a cumulative manner. A researcher meeting is held as necessary to assess the risks and benefits of the study.

Severe adverse events and unexpected events will be reported to the ethics committee and relevant authorities. Researchers in charge will regularly conduct a cumulative review of all adverse events, and if necessary, a meeting will be convened to assess the risks and benefits of the study.

Audits

Cell preparations provided by the sponsor must comply with relevant regulations and conditions, and a strict quality control check will be performed. During clinical research, a project monitor appointed by the trial sponsor will regularly visit the trial center to ensure strict adherence to the study protocol and correct completion of all CRFs. Laboratory tests will be performed by trial centers in accordance with standard operating procedures. Clinical laboratories in the trial center must carry out indoor quality control following relevant regulations and obtain quality evaluation certification from the Clinical Laboratory of the Ministry of Health.

For clinical treatment with NSCs, there must be at least one physician with a professional title of deputy senior rank, two attending physicians, one nurse with a professional title of deputy senior rank, and two nurses in charge. All medical staff should be proficient in aseptic technique and first aid skills. Cell preparation technicians should be healthy without infectious diseases and have more than 3 years of experience in Good Manufacturing Practice (GMP) grade cell culture. Preparation of autologous NSCs will be performed in a GMP-grade laboratory. The GMP laboratory complies with the Cleanroom Construction and Acceptance Specification and Pharmaceutical Manufacturing Quality Management Regulations (2010 Revision) and has been approved by a third-party organization. Equipment required for the preparation of autologous NSCs will include standardized products approved by relevant national authorities. The equipment will be regularly maintained, parameterized, and evaluated for technical advancement, applicability, energy saving, environmental protection, and operability, as well as service life. Final autologous NSC products will be screened for bacteria, fungi, mycoplasma, endotoxin, cell phenotype, and vigor before infusion into patients.

All patients included in the trial will receive free treatment and follow-up examinations and receive transportation cost subsidies. The trial will provide patients with clinical trial liability insurance. The insurance company bears treatment costs and financial compensation for trial-related injuries or deaths.

Ethics and dissemination

During clinical research, it is necessary to provide adequate protection for the subject's personal rights and ensure the scientific validity of the research. More considerations will be given to subject's rights, safety and health, rather than scientific and social benefits. This study has been approved by the Medical Ethics Committee of the Affiliated Hospital of Xuzhou Medical University, China (approval number: XYFY2017-KL052-01) (Additional file 1 [Additional file 1]). During the course of this clinical trial, any modification of the study protocol will include obtaining approval from the medical ethics committee. Any severe adverse event that occurs during the clinical trial will be reported to medical ethics committee in a timely manner.

Written informed consent will be obtained from patients or their legal guardians after the researchers or appointed representatives fully explain the details of the clinical study. Subsequently, researchers will be allowed to view, analyze, verify, and copy the important records of this study. The subject's personal identifiers and sponsor's intellectual property will be confidential. This manuscript is prepared and modified according to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) guidelines (Additional file 2 [Additional file 2]). Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be published at www.figshare.com.


  Discussion Top


Past contributions and existing problems of other scholars in this field of research

In preliminary experiments, embryonic stem cells, fetal brain tissue, genetically modified immortalized NSC lines, and autologous NSC transplantation were used for treatment of PD in animal models, and animal behaviors were greatly improved (Bjorklund et al., 2002; Takagi et al., 2005; Tian et al., 2011; Zhang et al., 2011; Han et al., 2012). Evidence also supports that NSC transplantation can effectively improve the neurological function of PD patients, but sample sizes are small, follow-up times are short, and a parallel control group is lacking (Chen et al., 2012; Kefalopoulou et al., 2014).

Novelty of this study

In this study, we will use a conventional drug as a control. The efficacy of autologous NSC transplantation for the treatment of PD will be evaluated at 36 months post-treatment. At the same time, therapeutic efficacy will be compared between intrathecal and intravenous administration routes.

Limitations of this study

Randomized grouping will not be used. The results of this preliminary study are likely to be biased because of the small sample size. The whole sample will be completed later. Multi-center, parallel-group, double-blind, randomized controlled clinical trials involving a larger sample will be performed to provide more valuable objective evidence.

Significance of this study

Results of this study will provide small sample clinical evidence for intrathecal and intravenous administration of autologous NSCs for treatment of PD.


  Trial Status Top


The study protocol was designed in July 2017. Ethical approval of clinical trial was obtained on December 22, 2017 and registered on December 25, 2017. Patient recruitment began in January 2018 and will be ended in January 2019. Each patient will be followed up for 36 months. Follow-up will be completed in January 2022. Data analysis will be performed in July 2022.

Additional files

Additional file 1: Ethical approval document.

Additional file 2: SPIRIT checklist.

Author contributions

DQG conceived and designed the study protocol. DQG and TX will guide the clinical trial. HMD will be responsible for details of the study protocol. MRW and XYL will be responsible for cell preparation. YFM will be in charge of recruitment. XLW will evaluate clinical data. JML will nurse the patients. All authors approved the final version of the manuscript for publication.

Conflicts of interest

There are no conflicts of interest to declare.

Financial support

None.

Institutional review board statement

This study protocol will be performed in strict accordance with the Declaration of Helsinki. Ethics approval from Medical Ethics Committee of the Affiliated Hospital of Xuzhou Medical University of China was achieved on December 22, 2017 (approval No. XYFY2017-KL052-01).

Declaration of patient consent

The authors certify that they will obtain patient consent forms. In the form, patients will give their consent for their images and other clinical information to be reported in the journal. The patients will understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Reporting statement

This study follows the Transparent Reporting of Evaluations with Nonrandomized Designs (TREND) statement and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.

Biostatistics statement

The statistical methods of this study were reviewed by the biostatistician of the Affiliated Hospital of Xuzhou Medical University, China.

Copyright transfer agreement

The Copyright License Agreement has been signed by all authors before publication.

Data sharing statement

Individual participant data that underlie the results reported in this article, after deidentification (text, tables, figures, and appendices) will be available. Study protocol, informed consent, and clinical study report will be available in September 2020. Results will be disseminated through presentations at scientific meetings and/or by publication in a peer-reviewed journal. Anonymized trial data will be available indefinitely at http://www.jsxyfy.com.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

 
  References Top

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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