Does early injection of mouse nerve growth factor affect motor and cognitive abilities in high-risk infants? study protocol for a randomized parallel-controlled trial
Lin Du, Ling Shan, Xiao-Jing Yue, Hong-Hua Li, Fei-Yong Jia M.D.
Department of Developmental Behavioral Pediatrics, The First Hospital of Jilin University, Changchun, Jilin Province, China
|Date of Web Publication||15-May-2018|
Department of Developmental Behavioral Pediatrics, The First Hospital of Jilin University, Changchun, Jilin Province
Source of Support: None, Conflict of Interest: None
Background and objectives: Newborns with perinatal risk factors and abnormal general motor quality assessment are at high risk of developing cerebral palsy. The treatment is earlier, the prognosis is better. This trial will investigate whether, combined with conventional early interventional therapy, the use of mouse nerve growth factor in high-risk infants can improve their motor and cognitive abilities.
Design: This is a prospective, single-center, randomized, parallel, controlled, clinical trial.
Methods: This trial will be conducted in the Department of Developmental Behavioral Pediatrics, the First Hospital of Jilin University, China. One hundred high-risk infants meeting the inclusion criteria will be recruited and randomized into control and treatment groups. Only participants in the treatment group will undergo the early treatment of mouse nerve growth factor via gluteus maximus injections, 20 μg per dose, once a day, 10 consecutive days per month. The treatment will last for 6 months. Both groups will receive standard early intervention therapies.
Outcome measures: The primary outcome measure is the incidence of the developmental disorders cerebral palsy and non-cerebral palsy at the actual age or corrected age of 12 months. The secondary outcome measures are Gesell Developmental Schedule scores at the actual age or corrected age of 12 months, Gross Motor Function Measure score at 6 and 12 months of treatment, and adverse events during the trial.
Discussion: If treatment with mouse nerve growth factor is found to be safe and effective for the high-risk infants, new options for the early-stage clinical treatment for such infants may be developed.
Ethics and dissemination: This trial has been approved by the Ethics Committee of First Hospital of Jilin University of China [approval number: 2017 (2017-290)]. This trial was designed in August 2017. Ethics approval was done in October 2017. This trial was registered in November 2017. The recruitment of subjects began in December 2017. Data analysis will be finished in December 2021. The results of the trial will be reported in a scientific conference or disseminated in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.
Trial registration: This trial has been registered in the Chinese Clinical Trial Registry (registration number: ChiCTR-IPR-17012774). Protocol version (2.0).
Keywords: cerebral palsy; non-cerebral palsy developmental disorders; nerve growth factor; qualitative assessment of general movements; Gross Motor Function Measure score; Gesell Developmental Schedules; randomized controlled trial
|How to cite this article:|
Du L, Shan L, Yue XJ, Li HH, Jia FY. Does early injection of mouse nerve growth factor affect motor and cognitive abilities in high-risk infants? study protocol for a randomized parallel-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis 2018;3:74-80
|How to cite this URL:|
Du L, Shan L, Yue XJ, Li HH, Jia FY. Does early injection of mouse nerve growth factor affect motor and cognitive abilities in high-risk infants? study protocol for a randomized parallel-controlled trial. Asia Pac J Clin Trials Nerv Syst Dis [serial online] 2018 [cited 2021 May 12];3:74-80. Available from: https://www.actnjournal.com/text.asp?2018/3/2/74/232080
| Introduction|| |
There are many factors affecting brain development in high-risk infants during the fetal, childbirth, and neonatal periods. High-risk infants are most likely to develop cerebral palsy. These newborns may experience central coordination disorders, brain injury syndrome, mental retardation, behavioral disorders, language barriers, hearing disturbances, visual disorders, and epilepsy (Byrne et al., 2017). The earlier the treatment of nervous system injury, the lower the incidence of neurodevelopmental injury and the greater the reduction in the degree of disability in high-risk infants. Therefore, early assessment and treatment of high-risk infants is very important (Takenouchi et al., 2010; Agut et al., 2014; Novak et al., 2017).
General motor quality assessment (GMs) can reliably predict severe neurological developmental disorders such as cerebral palsy within 3–4 months after birth. Studies have found that coherent spasm-synchronous general movements and lack of fidgety movements often indicate the development of spastic cerebral palsy after birth (Kepenek-Varol et al., 2016; Ricci et al., 2017; Rosenbloom, 2018).
Nerve growth factor is a cell growth regulator extracted from mouse submaxillary glands, snake venom, or human placenta (Paoletti et al., 2015). Mouse nerve growth factor is ~90% homologous with human nerve growth factor and the extraction process is relatively simple (Paoletti et al., 2015), so it is the main nerve growth factor currently used clinically. Huang et al. (2004) verified that mouse nerve growth factor can effectively improve limb motor dysfunction caused by toxic peripheral nerve injury and promote nerve recovery, without severe adverse events. Mouse nerve growth factor also has the dual biological functions of neuronal nutrition and promoting neurite growth, contributes to the repair of the damaged nervous system, and has a therapeutic effect on various brain diseases (Pierucci et al., 2001). Studies regarding mouse nerve growth factor in the treatment of cerebral palsy are shown in [Table 1].
|Table 1: Previous clinical studies investigating mouse nerve growth factor for the treatment of cerebral palsy|
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Novelty of this study
Previous studies have focused on the use of mouse nerve growth factor in children diagnosed with cerebral palsy (Chen, 2016; Feng et al., 2016; He, 2016; Tang, 2016a, b; Huang et al., 2017; Liu, 2017; Quan et al., 2017; Tang and Lei, 2017; Zeng et al., 2017). There has been no reliable randomized controlled trial on its use for the treatment of high-risk infants. Early diagnosis and intervention are required in fetuses with high-risk factors and abnormal whole-body performance during the perinatal period, and in infants at high-risk postnatally. This trial will investigate the use of mouse nerve growth factor in such high-risk infants.
The aim of this trial is to compare Gross Motor Function Measure scores, Gesell Developmental Schedule scores and the incidence of the developmental disorders cerebral palsy and non-cerebral palsy between control and treatment groups. We will investigate the effect of mouse nerve growth factor on improving the motor and cognitive abilities of high-risk infants.
| Methods/Design|| |
This trial will be conducted in the Department of Developmental Behavioral Pediatrics, the First Hospital of Jilin University, China. One hundred high-risk infants meeting the inclusion criteria will be recruited and equally randomized into control and treatment groups. Both groups will receive standard early intervention therapies with participants in the treatment group also receiving gluteus maximus injections of mouse nerve growth factor over 6 months, 20 μg per dose, once a day, 10 consecutive days per month. The primary outcome measure is the incidence of the developmental disorders cerebral palsy and non-cerebral palsy at the actual age or corrected age of 12 months. The secondary outcome measures are Gesell Developmental Schedule scores at the actual age or corrected age of 12 months, Gross Motor Function Measure scores after 6 and 12 months of treatment, and adverse events during the trial.
Our recruitment notice, containing details of the study, will be posted on the bulletin board of out-patient clinic and admission office of the Department of Developmental Behavioral Pediatrics, First Hospital, Jilin University, China. Guardians or legal representatives of high-risk infants who are interested in participating in the study can contact the person in charge of the project by telephone, email, or WeChat.
High-risk infants from the Department of Developmental Behavioral Pediatrics, First Hospital, Jilin University, China will be recruited.
Patients who meet all of the following criteria will be considered for study inclusion:
- High-risk factors during the perinatal period, such as preterm birth, neonatal asphyxia, hypoxic-ischemic encephalopathy, neonatal jaundice, neonatal intracranial hemorrhage, and neonatal cerebral infarction during or after childbirth
- Spasm-synchronous general movements or lack of fidgety movements in qualitative assessment of general movements in the perinatal period (Kepenek-Varol et al., 2016; Ricci et al., 2017; Rosenbloom, 2018)
- Age or corrected age < 15 weeks, irrespective of sex (the corrected age is the difference between actual age and preterm birth age; the motor and intellectual development in preterm infants should be judged according to the corrected age)
- Provision of written informed consent by guardian or legal representative
Patients who meet one or more of the following conditions will be excluded from the study:
- Genetic and metabolic diseases
- Important organ failure or critical condition
- Participation in other clinical trials
Patients who meet one or more of the following conditions will be withdrawn from the study:
- Incomplete data that affect efficacy evaluation
- Complications affecting efficacy assessment and diseases affecting outcomes during the trial
- Unable to determine efficacy due to the combination of other therapies or medicines that accelerate the efficacy
Randomization and blinding
High-risk infants meeting the inclusion and exclusion criteria will be coded sequentially at admission. Then the evaluator will randomly select a number in a random number table, from this number, beginning to copy random numbers in the table in any direction. The number of random numbers copied will be as same as the number of participants. The random numbers that are checked will be labeled below the code of participants. Odd numbers will be assigned to the control group, and even numbers to the treatment group. The grouping scheme will be hidden in opaque envelopes. The evaluator will be blind to the group assignment.
Conventional early interventions in the control and treatment groups
Each participant in two groups will receive additional stimulation and/or environmental change stimulation, for 30 minutes a day, 6 days a week, for 6 consecutive months. These therapies will be performed by professional rehabilitation therapists. The order of the interventions can be changed.
Auditory stimulation: Using a variety of sounds (such as sand hammer and bell), the children will attempt to find the sound source at a certain distance from their ear. Additionally, the experimenter will gently tell stories, sing children's songs, call the child by name, and talk about things related to the child.
Visual stimulation: The children will chase brightly colored objects. According to the child's age, the scope of the pursuit will be gradually increased. The children will also be encouraged to follow the smiling faces of their parents.
Tactile stimulation: After placing the hand in the mouth, the experimenter will properly assist in eating hand movements. The hand will grasp objects of various sizes, shapes, and textures.
Taste stimulation: A range of flavors will be tasted through mouth feeding.
Action and functional stimulation: Early anti-gravity training, mobility training, position conversion training; lower limb kicks of toys while in the supine position; column-shaped toy grasping after the forearm is rotated backwards; operating a toy with both hands; hand grasps of an object and putting it in the mouth; hands following toys in all directions.
Oral massage: The external part and oral cavity of the mouth is massaged, inducing the original reflection.
Injection of nerve growth factor in the treatment group
Mouse nerve growth factor (trade name: Jinlujie; approval number: GYZZ S20060051; Wuhan Hiteck Biological Pharma Co., Ltd., Wuhan, China) will be injected into the gluteus maximus, 20 μg per dose, once a day, 10 consecutive days per month, for 6 consecutive months.
Professionally trained experienced physicians from the Department of Developmental Behavioral Pediatrics, First Hospital, Jilin University, China will perform the assessments blinded.
Primary outcome measure
The incidence of developmental disorders of cerebral palsy and non-cerebral palsy at the actual age or corrected age of 12 months will be calculated.
The diagnostic criteria for cerebral palsy contain four necessary conditions and two reference conditions [Table 2].
Secondary outcome measures
- Gesell Developmental Schedules at the age or corrected age of 12 months: Gesell Developmental Schedules proposed by Arnold Gesell can mainly diagnose the ability of five aspects: Gross movement, fine movement, adaptability, speech, and personal-society. Low Gesell Developmental Schedules score indicates poor development (Ball, 1977).
- Gross Motor Function Measure score at 6 and 12 months of treatment: The Gross Motor Function Measure can effectively measure the development of gross motor function. Developed by Russell et al. (1989), it includes 88 items. Higher Gross Motor Function Measure scores represent better gross motor function (Reid et al., 2011).
- Adverse events: In previous clinical trials, pain at the injection site, occasional urticaria, and increased neutrophils appeared after injection of mouse nerve growth factor. During this trial, any adverse event will be recorded in detail and followed. The total incidence of adverse events will be calculated. An adverse event will be defined as any unfavorable medical event during the trial, regardless of whether it is directly associated with the use of mouse nerve growth factor. An adverse event can therefore be any unfavorable and unexpected sign (including abnormalities in laboratory findings), symptom, or disease temporally coinciding with, but not necessarily related to, the use of mouse nerve growth factor.
Generally, the relationship between an adverse event and the mouse nerve growth factor will be categorized as definitely related, probably related, possibly related, possibly unrelated, and definitely unrelated. The adverse events related to the clinical use of mouse nerve growth factor will be analyzed. In the case of an adverse event, the researchers will be liable to review all relevant records (e.g., course history, laboratory data, and diagnostic reports) and record the event-related information in a case report form.
Researchers will evaluate the patient's symptoms, disease signs, and other clinical data. The diagnosis will be recorded as an adverse event or a serious adverse event rather than signs/symptoms.
The details of the measures taken to manage adverse events will be recorded in the original documents and case report forms. Proper therapeutic measures will be taken if a severe adverse event occurs, to protect the rights and interests of the subjects. If necessary, the Ethics Committee will have the right to terminate the trial immediately. At the end of the trial, the subjects, sponsors, and Ethics Committee will be informed of the adverse events and their causes and explanations. In addition, the adverse events will be reported to the China Food and Drug Administration and Jilin Food and Drug Administration within 24 hours.
[Figure 1] shows the flow chart of the study protocol. The schedule of outcome measurement assessments is shown in [Table 3].
In accordance with our experience and previous results (Hong et al., 2017), we hypothesize that the incidence of developmental disorders of cerebral palsy and non-cerebral palsy will be 40% and 70% in the treatment group and the control group, respectively; that is, the efficacies will be 60% and 30%. Taking β = 0.1 with a significance level of α = 0.05, the final effective sample size of n = 57 per group will be calculated using PASS 11.0 software (PASS, Kaysville, UT, USA). If we assume a loss rate of 10%, we will require 63 cases per group. Fifty subjects will be recruited in phase I clinical trial, and the remaining will be recruited in phase II clinical trial.
General condition of high-risk infants, Gross Motor Function Measure score and Gesell Developmental Schedules score will be analyzed using SPSS 23.0 software (IBM Corp., Armonk, NY, USA). Measurement data will be expressed as the mean ± SD. Enumeration data will be represented by the percentage. Demographics and baseline indicators of high-risk infants will be analyzed using descriptive statistics. The incidence of developmental disorders of cerebral palsy and non-cerebral palsy, Gesell Developmental Schedules and Gross Motor Function Measure will be compared using one-way analysis of variance. Results will be analyzed according to the intention-to-treat principle.
Data collection and management
Research information will be re-identified. That is, after deleting the participant's name, each subject will be given a special number. Only the research team can match the participant's name with their code number. All electronic data will be stored confidentially and will only be accessed through a password. A backup will be made on your computer to ensure that all data will be secured. Any copy of the data will only be identified by numbers and stored in a locked file cabinet. The Department of Developmental Behavioral Pediatrics of First Hospital of Jilin University of China will preserve all of the data regarding this trial. Subjects’ information provided in a speech or publication produced by this trial will be in an unrecognizable manner. The data will be presented as grouped data.
To ensure maximum consistency of results, all children's exercise assessment and development scale assessment will be performed by experienced physicians who are professionally trained in the Department of Developmental Behavioral Pediatrics, First Hospital, Jilin University, China. Data processing and statistical calculations will be completed by professional statisticians. The staff from the Department of Developmental Behavioral Pediatrics will serve as an auditor, which will be responsible for confirming whether the records and reports of all data are correct and complete, and whether all report forms are correct and consistent with the original data.
The high-risk children participating in the trial will receive free inspection and evaluation during the follow-up, and will be given certain compensation for transportation fee. When a test-related injury occurs, relevant institutions and researchers will be obliged to provide emergency medical assistance. The related costs will be provided by clinical trial liability insurance.
Ethics and dissemination
This trial has been approved by the Ethics Committee of First Hospital of Jilin University of China [Additional file 1 [Additional file 1]; approval number: 2017 (2017-290)]. Guardian or legal representative of high-risk infants will provide informed consent. The writing and editing of the article will be performed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) (Additional file 2 [Additional file 2]). The results of the trial will be reported in a scientific conference or disseminated in a peer-reviewed journal. Anonymized trial data will be available indefinitely at www.figshare.com.
This trial was designed in August 2017. Ethics approval was done in October 2017. This trial was registered in November 2017. The recruitment of subjects began in December 2017. Data analysis will be finished in December 2021.
| Discussion|| |
Contributions and problems of previous studies in this field
Mouse nerve growth factor and human nerve growth factor are highly homogenous (Paoletti et al., 2015). Mouse nerve growth factor has been used in the treatment of limb motor dysfunction caused by peripheral neuropathy and in the treatment of various brain diseases (Zeng et al., 2010; Fan et al., 2014; Xu et al., 2014). However, no randomized controlled trials have been conducted using it to treat high-risk infants. In clinical settings, Chinese scholars observed that the long-term motor function of high-risk children treated with mouse nerve growth factor and rehabilitation was markedly improved compared with the control group (Yan et al., 2005). Therefore, we believe that the application of mouse nerve growth factor combined with rehabilitation will enhance the motor function of children with central nervous system injury, and we expect that their cognitive capabilities will also improve.
Characteristics of this study protocol
This study mainly focuses on high-risk infants, that is, those without clear diagnoses. Early diagnosis and treatment should be carried out to reduce the risk of the developmental disorders cerebral palsy and non-cerebral palsy. This trial design adopts a strict prospective randomized controlled trial method. Outcome data can be an effective basis for clinical treatment.
Limitations of this study protocol
(1) This trial will only compare the efficacies of mouse nerve growth factor combined with basic treatment and early intervention alone. However, citicoline, cerebrolysin, and monosialotetrahexosyl ganglioside sodium are currently used for the treatment of high-risk infants. It is also necessary to compare and analyze the difference in the efficacies of mouse nerve growth factor and these drugs to adapt to the clinical actual situation; (2) small sample size of high-risk infants; and (3) lack of long-term follow-up as high-risk infants will only be followed for 12 months.
Significance of this study protocol
The trial will provide objective indicators for clinical trials for nerve growth factor in improving motor and cognitive capabilities, and reducing the incidence of the developmental disorders cerebral palsy and non-cerebral palsy, in high-risk infants.
| Trial Status|| |
Patient recruitment is ongoing.
Additional file 1: Ethical approval document.
Additional file 2: SPIRIT checklist.
Manuscript writing and literature searching: LD. Design of early intervention: LS. Data arrangement: XJY. Design of efficacy assessment: HHL. Design of study protocol: FYJ.
Conflicts of interest
The interventions in this trial will apply mouse nerve growth factor (Wuhan Hiteck Biological Pharma Co., Ltd., China), but all authors state that they do not receive relevant financial support and there is no conflict of interest.
Institutional review board statement
All protocols will be performed in accordance with the Ethical Principles for Medical Research Involving Human Subjects in the Declaration of Helsinki. This trial has been approved by the Ethics Committee of First Hospital of Jilin University of China [approval number: 2017 (2017-290)] on 14 September 2017.
Declaration of participant consent
The authors certify that they will obtain all appropriate participant consent forms. In the form the participants’ legal guardians will give their consent for participants’ images and other clinical information to be reported in the journal. The legal guardians understand that the infants names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
This study follows the Consolidated Standards of Reporting Trials (CONSORT) statement and Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidance for protocol reporting.
The statistical methods of this study were reviewed by the biostatistician of the First Hospital of Jilin 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 in particular shared. Study protocol and informed consent form will be available within 6 months after completion of the trial. 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 www.figshare.com.
Checked twice by iThenticate.
Externally peer reviewed.
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[Table 1], [Table 2], [Table 3]