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STUDY PROTOCOL
Asia Pac J Clin Trials Nerv Syst Dis 2018,  3:1

Umbilical cord mesenchymal stem cell and neural stem cell therapy for cerebral palsy: study protocol for a randomized, parallel-controlled trial


First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province, China

Date of Web Publication8-Mar-2018

Correspondence Address:
Jing Liu
First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning Province
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2542-3932.226187

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  Abstract 

Background and objectives: Cerebral palsy is the most common cause of dyskinesia in children and is not curable by generalized rehabilitation, pharmacotherapy, Chinese medicine, exercise therapy, or surgery. To date, several case reports have demonstrated that umbilical cord mesenchymal stem cells (UCMSCs)/neural stem cells (NSCs) have a therapeutic role in children with cerebral palsy; however, there has been no large-sample clinical trial to verify this. Therefore, there is a need to evaluate the safety and effectiveness of UCMSCs/NSCs for the treatment of cerebral palsy in children.
Design: A prospective randomized parallel-controlled trial.
Methods: One hundred and ten children with cerebral palsy who will receive treatment in the First Affiliated Hospital of Dalian Medical University, China, will be randomly divided into five groups (n = 22 per group): control, nasal transplantation of UCMSCs, lumbar puncture transplantation of UCMSCs, nasal transplantation of NSCs, and lumbar puncture transplantation of NSCs. Cell transplantation will be correspondingly conducted in the latter four groups, with at least 1 × 107 cells per session, for two sessions within 4 weeks as one course, for a total of two courses.
Outcome measures: Evaluations will be performed before cell treatment and at 1, 3, 6, 9, and 12 months after the completion of two treatment courses, including Gross Motor Function Measure (GMFM)-88, GMFM-66, Fine Motor Function Measure (FMFM), Modified Ashworth Scale, the Gesell Developmental Schedules, electroencephalogram examination and brain imaging examination. The primary outcome of this study is the overall objective response rate calculated on the basis of the changes in GMFM-88 total score and GMFM-66 reference percentile. The secondary outcomes of this study include the duration of response and progression-free survival based on the GMFM-88 total score change and GMFM-66 percentile change as well as overall survival, FMFM score, Modified Ashworth Scale score, the Gesell Developmental Schedules score, electroencephalogram examination and brain imaging examination.
Discussion: This study aims to verify the efficacy and safety of UCMSCs/NSCs transplantation for the treatment of cerebral palsy in children, providing experimental data to support UCMSCs/NSCs therapy for cerebral palsy in clinical practice.
Ethics and dissemination: Written informed consent will be given by legal guardians or authorized surrogates of children with cerebral palsy as well as donors or their legal guardians. Design of the trial was completed in November 2016, and registered with ClinicalTrials.gov in December 2016. Participant recruitment was initialized in March 2017, and is expected to last 2 years. Data collection and follow-up visit will end in June 2020, and data analysis will be completed in December 2020. The results of this study will be disseminated by publications in peer-reviewed journals.
Trial registration: This trial was registered in the ClinicalTrials.gov with registration No. NCT03005249 on December 26, 2016.

Keywords: stem cell transplantation; umbilical cord mesenchymal stem cells; neural stem cells; cerebral palsy; Gross Motor Function Measure; randomized, parallel-controlled trials; clinical trials


How to cite this article:
Liu J, Han J, Ma Ly, Lian Zg, Li Y, Li Xy, Wei Wj, Han C, Zhao Jy, Guan X. Umbilical cord mesenchymal stem cell and neural stem cell therapy for cerebral palsy: study protocol for a randomized, parallel-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:1-9

How to cite this URL:
Liu J, Han J, Ma Ly, Lian Zg, Li Y, Li Xy, Wei Wj, Han C, Zhao Jy, Guan X. Umbilical cord mesenchymal stem cell and neural stem cell therapy for cerebral palsy: study protocol for a randomized, parallel-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2018 Jun 24];3:1-9. Available from: http://www.actnjournal.com/text.asp?2018/3/1/1/226187


  Introduction Top


Background

Cerebral palsy is the most severe lifelong disability disease and the most common cause of dyskinesia in childhood, characterized by sustained central movement and postural disorders, and activity restriction (Feng et al., 2016; Graham et al., 2016; Trevizol and Cordeiro, 2016; Wang et al., 2016b). The incidence of cerebral palsy was reported as 1.54–4% (No authors listed, 2002; Winter et al., 2002; Bhasin et al., 2006; Paneth et al., 2006; Arneson et al., 2009). Studies have reported that cerebral palsy may be caused by intrauterine infection, premature birth, asphyxia, and/or heredity factors (Ellenberg and Nelson, 2013; Burton, 2015; Nelson and Blair, 2015). Main therapies for cerebral palsy include comprehensive rehabilitation therapy, drug therapy, exercise therapy, and surgical methods (Novak et al., 2013; Jin et al., 2015; Zhang et al., 2015a), but to date there is no cure.

Stem cells are pluripotent cells with the ability to repair damaged tissues that have been used in the treatment of neurological and immune system diseases (Rosemann, 2014; Wang et al., 2016a). Umbilical cord mesenchymal stem cells (UCMSCs) are pluripotent stem cells that present in the umbilical cord of a newborn (Hollweck et al., 2012), and neural stem cells (NSCs) are stem cells capable of dividing and self-renewing in the nervous system (Bergstrom and Forsberg-Nilsson, 2012). These two types of cells can differentiate into nerve cells and participate in repair of the damaged nervous system (Thomaidou, 2014; Zhao et al., 2017). Currently, several case reports have indicated that UCMSCs/NSCs have therapeutic effects on cerebral palsy in children (He et al., 2012; Wang et al., 2013, 2015b). Nonetheless, there have been no large-sample clinical trials to verify this.

Features of this study

Recent clinical trials performed in countries outside China have demonstrated that stem cell therapy is likely to be the most effective method to treat cerebral palsy. Seventeen trials of stem cell therapy for cerebral palsy have been registered with ClinicalTrials.gov [Table 1]. In China, however, there are no standardized registered trials for stem cell therapy to treat cerebral palsy.
Table 1: Clinical trials registered at ClinicalTrials.gov addressing stem cell therapy for cerebral palsy

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Relevant studies by the author's group are shown in [Table 2].
Table 2: Stem cell therapy used by the author's group in the previous studies

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Objectives of this study

In this study, we aim to evaluate the safety and efficacy of UCMSCs/NSCs for the treatment of children with cerebral palsy by assessing motor function, muscle tone, development and complications during the treatment.



[TAG:2]Methods/Design[/TAG:2]

Study design

A prospective, randomized, parallel-controlled trial will be conducted in the First Affiliated Hospital of Dalian Medical University in China. The study population comprises 110 children with cerebral palsy who will be randomized into five groups (n = 22 per group): control, nasal transplantation of UCMSCs, lumbar puncture transplantation of UCMSCs, nasal transplantation of NSCs, and lumbar puncture transplantation of NSCs. Patients in the latter four groups will undergo corresponding cell transplantation for two sessions (at least 1 × 107 cells per session) within 4 weeks as one course, for a total of two courses. Evaluations will be performed before cell treatment and at 1, 3, 6, 9, and 12 months after the completion of two treatment courses, including Gross Motor Function Measure (GMFM)-88, GMFM-66, Fine Motor Function Measure (FMFM), Modified Ashworth Scale, the Gesell Developmental Schedules, electroencephalogram examination and brain imaging examination. The primary outcome is the overall objective response rate calculated on the changes in GMFM-88 total score and GMFM-66 reference percentile. The secondary outcomes include duration of response and progression-free survival based on the GMFM-88 total score change and GMFM-66 percentile change as well as overall survival, FMFM score, Modified Ashworth Scale score, the Gesell Developmental Schedules score, electroencephalogram examination and brain imaging examination. Design of the trial was completed in November 2016, and the trial was registered with ClinicalTrials.gov in December 2016. Participant recruitment was initialized in March 2017, and is expected to last 2 years. Data collection and follow-up visit will end in June 2020, and data analysis will be completed in December 2020. The results of this study will be disseminated by publications in peer-reviewed journals.

Recruitment

Children who receive treatment in the neonatal and neurology departments and other relevant departments of the First Affiliated Hospital of Dalian Medical University will be introduced by attending physicians to voluntarily participate in the trial. Written informed consent will be given by legal guardians or authorized surrogates of children with cerebral palsy. After screening, eligible children will be enrolled in the study according to the inclusion and exclusion criteria.

Study population

UCMSCs donors

UCMSCs will be voluntarily provided by mothers giving birth at the First Affiliated Hospital of Dalian Medical University in China.

Inclusion criteria

Lying-in women who meet all of the following criteria will be considered for study inclusion:

  • Under the age of 35 years who have normal development and nutrition
  • Having normal results in hepatitis B, hepatitis C, syphilis, AIDS, TORCH tests
  • Having caesarean section with live births but no fetal deformity
  • Provision of informed consent from donors or their legal guardians regarding cell donation.


Exclusion criteria

Lying-in women presenting with one or more of the following conditions will be excluded from the study:

  • With malignant tumors and/or infectious diseases
  • With a family history of genetic diseases
  • With blood diseases and metabolic diseases
  • With abnormal chromosomes in an amniotic fluid test
  • Developing concomitant intrauterine infection during childbirth process
  • Defined to have infections with human specific virus, including HIV, HBV, HCV, HTLV, EBV, CMV, TPPA, or Treponema pallidum infection.


NSCs donors

NSCs will be voluntarily donated by women undergoing abortion at the First Affiliated Hospital of Dalian Medical University in China.

Inclusion criteria

Abortion women will be considered for inclusion according to the following criteria:

  • Healthy and negative for HIV, HBV, HCV, HTLV, EBV, CMV, and TPPA
  • Donated tissue is from an aborted embryo (medical waste) of 6–8 gestational weeks.
  • Provision of informed consent from donors or their legal guardians regarding cell donation.


Exclusion criteria

Abortion women who meet any of the following criteria will be excluded from the study:

  • With malignant tumors and infectious diseases
  • With blood diseases and metabolic diseases
  • Presenting with abnormal chromosomes in an amniotic fluid test
  • Developing concomitant intrauterine infection during childbirth process
  • With a history of infectious disease and a family history of genetic diseases


Cerebral palsy children

Cerebral palsy children who receive treatment at the First Affiliated Hospital of Dalian Medical University will be recruited.

Inclusion criteria

Cerebral palsy children meeting all of the following criteria will be considered for inclusion:

  • Definitely diagnosed with hypoxic-ischemic cerebral palsy (Hayes, 2010; Zarrinkalam et al., 2010)
  • Clinical manifestation of spastic quadriplegia
  • Gross Motor Function Classification System levels II–IV (Hayes, 2010; Zarrinkalam et al., 2010; Colver et al., 2014)
  • Age 1–5 years, of either sex


Exclusion criteria

Cerebral palsy children will be excluded from the study if they fulfill one or more of the following criteria:

  • With systemic diseases that can influence treatment or patient's compliance
  • With potentially life-threatening diseases involving various organ systems
  • With brain deformity
  • With uncontrolled epilepsy
  • Presence of behavioral disorders or mood disorders
  • With allergies from blood products
  • Suffering from infectious diseases
  • Having craniocerebral operations prior to screening
  • Participation in other clinical trials


Withdrawal criteria

Cerebral palsy children will be withdrawn from the study if they fulfill any of the following criteria:

  • With complications affecting the assessment of efficacy and safety and diseases affecting the outcome evaluation
  • Presence of neurodegenerative or autoimmune diseases during the trial
  • Inability to complete the follow-up


Baseline data collection

Baseline information collected at enrollment is shown in [Table 3].
Table 3: Patient's baseline data

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Randomization and blinding

A table of random numbers will be produced using SAS 9.0 software (SAS Institute Inc., Cary, NC, USA) and will be used to assign a number to each included patient according to the visiting sequence. Included patients will be equally randomized into the control, nasal transplantation of UCMSCs, lumbar puncture transplantation of UCMSCs, nasal transplantation of NSCs, or lumbar puncture transplantation of NSCs groups. Assessorsevaluating the outcomes will be blinded to the grouping.

Interventions

Stem cell preparation

Preparation of UCMSCs: umbilical cord tissue collected under sterile conditions will be cryopreserved with umbilical cord protection solution, washed and disinfected. The tissue sample will be pulverized into tissue pieces of 5–10 mm3 using a tissue crusher, and these pieces will be transferred and placed at the bottom of a culture flask containing culture medium that will be added along via the side wall of the culture flask. Then, the culture flask will be placed in a 37°C, 5% CO2 atmosphere. Cells will be passaged until they achieve 60% confluence. Following rinsing with PBS, digestion with trypsin substitute, centrifugation and removal of the supernatant, the sample will be resuspended in fresh medium, subcultured, cryopreserved until the cell number reaches 1 × 108, and then thawed in 37°C water. This will be followed by resuspension in saline and 7-minute centrifugation at 1,200 r/min. The supernatant will be discarded, and the sample will be washed with saline and centrifuged for 7 minutes. Subsequently, the supernatant will be discarded again. Finally, 3 × 107 cells will be resuspended with fresh saline supplemented with an appropriate volume of albumin.

Preparation of NSCs: complete embryos will be repeatedly rinsed with NSC-A02-04 in a 100 mm sterile Petri dish. The skin and bones of the head will be peeled back to open the cranial cavity and expose brain tissue followed by removal of the surrounding vascular membrane. The cerebral cortex will be separated and divided into tissue pieces of about 1 mm3. After standing for 5 minutes, the supernatant will be discarded and the sample will be digested at 35°C, incubated in a 5% CO2 incubator for 30 minutes, and centrifuged at 300 × g at 20°C for 5 minutes. The supernatant will be removed and the sample pipetted using NAS-A01 and centrifuged at 300 × g at 20°C for 5 minutes. NSC-A02-04 solution will be added to make a single cell suspension that will be counted and added into the NSCs culture medium. Cells at a density of 1 × 105/mL will be cultured at 35°C in the presence of 5% CO2 for 2–3 days, and then incubated in fresh human NSCs medium. One-third of the medium will be changed every 3 days. Neurospheres to be passaged will be digested, filtered and added into NSC-A02-07 solution, centrifuged at 300 × g at 20°C for 3 minutes. The supernatant will be removed and the sample will be resuspended with NAS-A01 solution, centrifuged at 300 × g at 20°C for 3 minutes, and continuously cultured in a 35°C, 5% CO2 incubator. The cell suspension will be adjusted to a final concentration of 2 × 106 cells/mL for cryopreservation. The cells will be then thawed in a 37°C water bath. The cell suspension will be pipetted into a preheated resuscitation solution, followed by washing with resuscitation solution and centrifugation at 500 × g for 3 minutes. After removing the supernatant, the NSC-A02-04 solution will be used to pellet the cells followed by mixing in Hibernation medium. Finally, the cells will be incubated at 35°C in the presence of 5% CO2, following adjustment of the cell density.

Two types of stem cells will be evaluated for quality according to the Guidelines for Quality Control of Stem Cell Preparations and Preclinical Studies (Trial), issued by the China Food and Drug Administration (2015). UCMSCs and NSCs will be identified according to Additional file 1. [Additional file 1]

Cell transplantation

Nasal transplantation: in the lateral position, the child's head will be tilted upwards to 45° and no less than 1 × 107 stem cells will be slowly injected the nasal cavity via a flexible tube for about 2 minutes. The child's head will remain immobilized for about 30 minutes after injection. The child will be given 0.6 mg/kg immunosuppressant cyclosporine the next day after surgery. Transplantation will be performed once every 2 weeks (at least 1 × 107 cells per session), 4 weeks as one course, for a total of two courses.

Transplantation via lumbar puncture: the child will lie on their side with no pillow, their back vertical to the bed, the head bent forwards towards the chest, and both hands holding their knees. The puncture point will be defined as the intersection of the posterior superior iliac connection and posterior midline (i.e., the spinous process gap of L4–5 segments). The child will be anesthetized using 2% Lidocaine. At least 1 × 107 stem cells will be slowly injected for 2 minutes via a syringe. The child's head will remain immobilized for about 30 minutes after injection. This will be followed by 0.6 mg/kg immunosuppressant cyclosporine the next day after surgery. Transplantation will be performed once every 2 weeks (at least 1 × 107 cells per session), 4 weeks as one course, for a total of two courses.

Outcome measures

Evaluations will be performed before cell treatment and at 1, 3, 6, 9, and 12 months after the completion of two treatment courses.

Primary outcome measure

The primary outcome measure of this study is the overall objective response rate, defined as the percentage of subjects with complete remission or partial remission based on the changes in GMFM-88 total score and GMFM-66 reference percentile at any time during the trial.

GMFM is a measure of quantizing time-dependent gross motor function of children with cerebral palsy, containing 88 items or 66 items. The 88 items in the GMFM-88 merge into 66 items constituting the GMFM-66. Each item is scored at 0–3 points according to the degree of completion. A higher score indicates better gross motor function in a child (Beckers and Bastiaenen, 2015; Salavati et al., 2015).

Secondary outcome measures

  • For subjects who experience complete or partial remission, the duration of response is defined as the time from the first record of complete remission or partial remission until disease progression or death.
  • Progression-free survival is defined as the time from randomization until disease progression or death from any cause.
  • Overall survival is defined as the time from randomization until death due to any cause.
  • FMFM is an important scale that reflects the level of development of fine motor function in cerebral palsy children aged 0–3 years, which is recommended by the Rehabilitation Center of the Children's Hospital of Fudan University in China. The scale consists of 61 items with a full score of 183. A higher score indicates the better fine motor function of a child (Xu et al., 2008).
  • Modified Ashworth Scale is considered a clinical measure of muscle tone, which was developed by Bohannon and Smith (1987). A higher score indicates a better muscle tone.
  • Gesell Developmental Schedules are a set of developmental metrics (63 items) and are a commonly used scale to outline children's development developed by Dr. Gesell and colleagues in 1940. The developmental quotient is determined as the percentage of development age to chronological age in a child. A lower score indicates worse development (Accardo, 2013).
  • Electroencephalogram examination
  • Brain imaging examination mainly consisting of computed tomography (CT) and magnetic resonance imaging (MRI) examinations


Safety assessment

During the trial, we will record a patient's general condition, vital signs, routine blood data, routine biochemical data, liver and kidney function, immune function indicators (CD3, CD4, CD8, Treg), electrocardiogram and tumor markers.

If the subject develops an adverse event or has to undergo medical rescue during the trial, the investigator should immediately discontinue the trial and report the adverse event or others to the academic and ethical committees of the stem cell research institute within 24 hours. All the details will be reported further to the national and provincial competent authorities responsible for clinical research on stem cells. Proper therapeutic measures should be performed if a severe adverse event occurs, and the details will be reported to the academic and ethical committees of the stem cell research institute within 15 days. Causes and measures taken for adverse events will be reported further to the national and provincial competent authorities in charge of clinical research on stem cells. More importantly, if the researchers give the view that the occurrence of adverse events has no reasonable possibility of a correlation with stem cell agents used in the trial, they must address other rational causes for the occurrence of severe adverse events. After the treatment of adverse events is over, an adverse event report form will be filled out by the responsible department and submitted to the office of the research as an archive.

The flow chart of the trial is shown in [Figure 1], and the schedule of outcome measurement assessments is shown in [Table 4].
Figure 1: Flow chart of the trial.
Note: The primary outcome of this study is the overall objective response rate calculated based on changes in GMFM-88 total score and GMFM-66 reference percentile. The secondary outcomes of this study include duration of response, progression-free survival based on the GMFM-88 total score change and GMFM-66 percentile change as well as overall survival, FMFM score, Modified Ashworth Scale score, the Gesell Developmental Schedules score, electroencephalogram examination and brain imaging examination. UCMSCs: Umbilical cord mesenchymal stem cells; NSCs: neural stem cells; GMFM: Gross Motor Function Measure; FMFM: Fine Motor Function Measure.


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Table 4: Timing of outcome assessment

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Sample size

  • For the primary endpoint of effectiveness, objective response rate and exact binomial distribution will be used to provide a point estimate with a 95% confidence interval and P value with a higher objective response rate than historical controls (10%).
  • Subjects with no response data in the full analysis set will be counted as showing no remission.
  • In total, 100 patients will be enrolled in the study, with 20 patients in each group. Assuming a patient loss rate of 10%, 110 patients will be enrolled overall. Sample calculations will be performed by the Department of Statistics, Dalian Medical University, China.


Statistical analysis

  • Statistical analysis will be performed by the Department of Clinical Biostatistics, the First Affiliated Hospital of Dalian Medical University.
  • Measurement data will be expressed as mean ± standard deviation, and numerical data as percentages.
  • Descriptive statistics will be used to describe demographic data (e.g., age, sex) and baseline characteristics of patients. For the primary endpoint of effectiveness, objective response rate and exact binomial distribution will be used to provide a point estimate with a 95% confidence interval and P value with a higher objective response rate than historical controls (10%).
  • For the endpoints of response duration, progression-free survival, and overall survival, Kaplan-Meier curves and median estimates will be performed as appropriate. Other indices will be subjected to tests for normality and homogeneity of variance. One-way analysis of variance will be used for normally distributed data with homogeneous variance. Wilcoxon two-sample rank sum test will be used for non-normally distributed data.
  • Alpha = 0.025 (one-sided) will be set for the hypothesis with a false positive rate in major validity testing.


Data collection and management

  • Patient data collected during the trial will be recorded in case report form. Both paper and electronic case report forms will be kept by the designated person responsible for data archiving and preservation. Because of data security and confidentiality, unauthorized persons will have no access to any clinical data.
  • Any change or correction made to the data in the paper case report form will retain the original legible record. The date of data change or correction, signature, and related explanation (if necessary) will be indicated.
  • Any data change, deletion or addition will be recorded by electronic management systems from the first data entry. An audit trail will be set and protected by the system. No artificial modification or editing will be allowed.
  • Statistical analysis will be performed by the professional statistician according to the trial scheme.
  • Clinical data will be kept by the researchers for 30 years, starting from the end of the clinical trial, and by the sponsors for 30 years, starting from the commercialization of stem cell preparations used in the trial.


Audits

The data monitoring committee composed of clinicians and biostatisticians is responsible for independently assessing the safety, scientific validity, and completeness of the clinical trial. All members will be independent of the sponsor and have no conflicts of interest of relevance to the trial.

All researchers involved in clinical practice are working at the First Affiliated Hospital of Dalian Medical University and have medical qualifications. They have abundant clinical experience and are familiar with the trial protocol and relevant laws and regulations. The research group will perform the clinical trial under conditions of good medical facilities, laboratory equipment, and personnel allocation, and has enough time to engage in clinical research.

The trial will be audited every 6 months, independent of the researchers and sponsors.

During the trial, a free policy to improve patient compliance will be implemented for physical examination and MRI review in enrolled children with cerebral palsy. The researchers should provide insurance coverage for subjects participating in the trial and cover the costs of treatment and financial compensation for subjects suffering damage or death associated with the trial.

Ethics and dissemination

  • This study was approved by the Ethics Committee of the First Affiliated Hospital of Dalian Medical University of China (approval No. LCKY2016-60; Additional file 2 [Additional file 2]).
  • This trial will follow the relevant laws and regulations of the Declaration of Helsinki, Revised CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects, and Stem Cell Clinical Research Management (Trial), as well as the hospital's relevant ethical principles.
  • This manuscript was prepared and modified according to the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines (Additional file 3 [Additional file 3]).
  • All the patients and their families will voluntarily participate in the trial, and all donors and recipient guardians or legal representatives will be fully informed of the experimental process. Written informed consent will be provided with the premise of fully understanding the treatment plan (Additional files 4, 5, 6 [Additional file 4]).
  • To keep individual privacy, all original data and relevant documents will be stored as confidential files for at least 30 years from the end of the trial.
  • The researchers from the Stem Cell Research Institute, the First Affiliated Hospital of Dalian Medical Univer sity have the right to obtain all raw data or research records. Anonymized trial data will be published at www.figshare.com.
  • The results of the trial will be disseminated in apeer-reviewed journal.



  Discussion Top


Contributions and existing problems

As a frontier biotechnology, the stem cell industry has been favored by the capital markets and pharmaceutical companies. In China, previous clinical research on stem cells has been chaotic, and there have been no standardized registered trials regarding stem cell therapy for cerebral palsy. Although UCMSCs/NSCs transplantation might have a therapeutic role in children with cerebral palsy, all previously reported cases have been of low sample number and cannot be used as a valuable basis for clinical treatment. To date, there is no large-sample clinical trial of UCMSCs/NSCs for the treatment of cerebral palsy in children.

Novelty of this study

In October 2016, the National Health and Family Planning Commission and the Food and Drug Administration of China jointly announced the premier clinical research institutions for stem cells (National Health and Family Planning Commission of China & China Food and Drug Administration, 2016). The First Affiliated Hospital of Dalian Medical University belongs to one of these institutions. Moreover, the hospital is also certificated as the National & Local Innovation Platform for Stem Cells and Regenerative Medicine by the National Development and Reform Commission of China, as well as the National Stem Cell Transplantation and Regenerative Medicine International Cooperation Base by the Ministry of Science and Technology of China. The author's team has set up a longitudinal research system targeting the upstream, midstream and downstream determinants of clinical transformation regarding stem cell therapy for nerve repair (Han et al., 2014; Wang et al., 2015a; Yin et al., 2015; Zhang et al., 2015b; Guan et al., 2016) and has developed an improved quality control system. The overall scheme and methods facilitate the clinical transformation process of stem cell therapy for nerve injury repair, providing a basis for stem cell therapy for cerebral palsy in clinical practice.

Based on ethical evaluation, human UCMSCs/NSCs will be used in the trial to address stem cell therapy for cerebral palsy children. The trial conducted in the First Affiliated Hospital of Dalian Medical University will fulfill the requirements of Stem Cell Clinical Research Management (Trial) and relevant international standards. The objective of this trial is to evaluate the safety and efficacy of UCMSCs/NSCs for the treatment of children with cerebral palsy by assessing the motor function, muscle tone, development and complications during the treatment. The trial will provide a new strategy for the clinical treatment of cerebral palsy. [41]

Limitation of this study

The trial will only observe the 12-month efficacy of cell transplantation, and further studies on the long-term effect are warranted.

Significance of this study

The trial will verify the effectiveness and safety of UCMSCs/NSCs transplantation in children with cerebral palsy, and provide clinical data for the future stem cell treatment of cerebral palsy.


  Trial Status Top


Patient recruitment is ongoing at the time of submission.

Author contributions

All authors participated in conception, design and implementation of the trial.

Conflicts of interest

The authors have stated that the work submitted for publication and the manuscript preparation were conducted in the absence of any influence of their positions on research opinion and data that could be perceived as a potential conflict of interest.

Financial support

None.

Research ethics

The protocols has been approved by the Ethics Committee of the First Affiliated Hospital of Dalian Medical University (approval No. LCKY2016-60). All the patients' legal guardians or authorized surrogates will voluntarily participate in the trial, and all donors and recipient guardians or legal representatives should be fully informed of the experimental process and provide written informed consent with the premise of fully understanding the treatment plan. Clinicians and the research institute involved in the trial will follow the relevant laws and regulations of the Declaration of Helsinki, the Revised CIOMS International Ethical Guidelines for Biomedical Research Involving Human Subjects, the Stem Cell Clinical Research Management (Trial) and relevant hospital's ethical principles.

Declaration of patient consent

The authors certify that they will obtain the consent forms of legal guardians or authorized surrogates of children with cerebral palsy as well as donors or their legal guardians. In the form, legal guardians or authorized surrogates of children with cerebral palsy as well as donors or their legal guardians will give their consent for patients images and other clinical information to be reported in the journal. The legal guardians or authorized surrogates of children with cerebral palsy as well as donors or their legal guardians will understand that the patients' names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Data sharing statement

The datasets analyzed during the current study will be available from the corresponding author on reasonable request.

Plagiarism check

Checked twice by iThenticate.

Peer review

Externally peer reviewed.

Additional files

Additional file 1: Criteria for evaluating the quality of stem cells.

Additional file 2: Approval for the ethical review of stem cell clinical research.

Additional file 3: SPIRIT checklist.

Additional file 4: Written informed consent of umbilical cord donors.

Additional file 5: Written informed consent of embryo donors.

Additional file 6: Written informed consent of stem cell clinical research.

 
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