Allogenic Umbilical Cord Blood and Erythropoietin Combination Therapy for Cerebral Palsy

Study Overview
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Brief Summary
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This randomized control study is aimed to determine efficacy of umbilical cord blood and erythropoietin combination therapy for children with cerebral palsy.

Detailed Description
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Cerebral palsy is a disorder of movement and posture that result from a nonprogressive lesion or injury of the immature brain. It is a leading cause of childhood onset disability through one's life. Umbilical cord blood(UCB) is suggested as therapeutic method for cerebral palsy which resulted from animal studies. Stem cells included in UCB is expected to exert therapeutic efficacy for functional recovery. It is also suggested that erythropoietin is useful to repair neurological injury in brain. The main mechanism of erythropoietin is supposed to be neuroprotection and neurogenesis which would reinforce the effect of stem cell as well. Although autologous umbilical cord would be safe, the children who have problems at birth seldom have autologous umbilical cord blood. Allogenic umbilical cord blood might be useful for these children if its effect is approved.

Official Title
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Double-blind Randomized Controlled Trial to Evaluate the Efficacy and Safety of a Combination Therapy of Allogenic Umbilical Cord Blood and Erythropoietin for Children With Cerebral Palsy

Conditions
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Cerebral Palsy

Intervention / Treatment
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* Biological: Umbilical Cord Blood Infusion
* Drug: Erythropoietin Injection
* Other: Active Rehabilitation
* Other: Placebo Umbilical Cord Blood
* Other: Placebo Erythropoietin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Known cerebral palsy Willing to comply with all study procedure Exclusion Criteria: High risk of pneumonia or renal function deterioration after using of immunosuppressant Presence of known genetic disease Possibility of drug hypersensitivity which is related to this study remedy History of previous cell therapy Poor cooperation of guardian,including inactive attitude for rehabilitation Intractable seizure disorder Autism

Ages Eligible for Study
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Minimum Age: 10 Months
Maximum Age: 10 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Umbilical Cord Blood & Erythropoietin & Rehabilitation<br>Allogenic umbilical cord blood infusion, erythropoietin injection & active rehabilitation | Biological: Umbilical Cord Blood Infusion<br>* The subjects will be undertaken allogeneic umbilical cord blood infusion (total nucleated cells > 3x10^7/kg) intravenously under non-myeloablative immunosuppression (maintaining blood level of cyclosporine as 100-200ng/mL for 1 month).<br>* Other names: Donated Umbilical Cord Blood Units from Affiliated Cord Blood Bank;Drug: Erythropoietin Injection<br>* Erythropoietin will be given as the schedule of twice a week for 4 weeks with the dosage of 500 IU/kg for 2 times intravenously and 250 IU/kg subcutaneously for 6 times.<br>* Other names: Brand name of Erythropoietin: Espogen (made by LG Life Science);Other: Active Rehabilitation<br>* All subjects should participate in active rehabilitation. They received two physical and occupational therapy sessions per day. Post discharge, each participant continued to receive rehabilitation therapy at least 3 days per week for additional 5 months.<br>|
| Active Comparator: Erythropoietin & Rehabilitation<br>Erythropoietin injection, active rehabilitation | Drug: Erythropoietin Injection<br>* Erythropoietin will be given as the schedule of twice a week for 4 weeks with the dosage of 500 IU/kg for 2 times intravenously and 250 IU/kg subcutaneously for 6 times.<br>* Other names: Brand name of Erythropoietin: Espogen (made by LG Life Science);Other: Active Rehabilitation<br>* All subjects should participate in active rehabilitation. They received two physical and occupational therapy sessions per day. Post discharge, each participant continued to receive rehabilitation therapy at least 3 days per week for additional 5 months.<br>Other: Placebo Umbilical Cord Blood<br>* Placebo Umbilical Cord Blood will be given except the Experimental arm. Placebo Umbilical Cord Blood was made using peripheral blood. Participants and Investigators maintained as blind.<br>* Other names: : 1.5 to 3 ml of the subject's own blood was collected and mixed with 15 to 20 ml of albumin.;|
| Placebo Comparator: Only Rehabilitation<br>Active rehabilitation | Other: Active Rehabilitation<br>* All subjects should participate in active rehabilitation. They received two physical and occupational therapy sessions per day. Post discharge, each participant continued to receive rehabilitation therapy at least 3 days per week for additional 5 months.<br>Other: Placebo Umbilical Cord Blood<br>* Placebo Umbilical Cord Blood will be given except the Experimental arm. Placebo Umbilical Cord Blood was made using peripheral blood. Participants and Investigators maintained as blind.<br>* Other names: : 1.5 to 3 ml of the subject's own blood was collected and mixed with 15 to 20 ml of albumin.;Other: Placebo Erythropoietin<br>* Placebo Erythropoietin containing Normal Saline<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Motor Performance | GMPM (Gross Motor Performance Measure) as a standardized measurement tool for assessing quality of movement regarding 3 properties of 5 ones; alignment, coordination, dissociated movement, stability, and weight shift (range: 0 100, Higher value means better motor quality). We reported changes of GMPM score between each assessment time points. Categories of outcome table are baseline and values of just subtracting the latter raw scores from the former ones. | Baseline -1 month - 3 months - 6 months | 
| Changes in Standardized Gross Motor Function | GMFM (Gross Motor Function Measure) as a standardized measurement tool for assessing Gross Motor Function consisting of sub-scales; lying & rolling, sitting, crawling & kneeling, standing, walking, running & jumping (range: 0 100 , Higher value means better gross motor function). We reported changes of GMFM between each assessment time points. Categories of outcome table are baseline and values of just subtracting the latter raw scores from the former ones. | Baseline - 1 month - 3 months - 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Cognitive Neurodevelopmental Outcome | Korean version of Bayley Scale of Infant Development-II (K-BSID-II) Mental Scales (higher value means better mental function: 0 - worst, 178 - best). We reported changes of BSID-II Mental Scale raw score between each assessment time points. Categories of outcome data are values of subtracting the latter scores from the former ones. | Baseline -1 month - 3 months - 6 months | 
| Changes in Motor Neurodevelopmental Outcome | Korean version of Bayley Scale of Infant Development-II (K-BSID-II) Motor Scales (higher value means better motor function: 0 - worst, 111 - best). We reported changes of BSID-II Motor Scale raw score between each assessment time points. Categories of outcome data are values of subtracting the latter scores from the former ones. | Baseline - 1 month - 3 months - 6 months | 
| Changes in Brain MRI | Changes on brain Diffusion Tensor Image (DTI); DTI provides quantitative information about the microscopic integrity of white matter. White matter normally possesses a high degree of diffusion anisotropy than gray matter. We can measure fractional anisotropy (FA) value in DTI imaging and it ranges from 0 to 1. Higher FA value of a certain region of interest means the area has more integrity of white matter. | Baseline - 6 months | 
| Comparison of Changes in Brain Glucose Metabolism Using by Brain 18F-FDG PET: Increased and Decreased Areas of Brain Glucose Metabolism | 18F-FDG PET imaging was performed twice prior to and then 2 weeks post-treatment. Ninety slices of each emission image were obtained, and all scans were reviewed by a nuclear physician. Spatial pre-processing and statistical analyses were performed using SPM8 implanted in Matlab to compare differences in regional brain glucose metabolism between groups and differences between pre- and post-therapy imaging data. We reported increased areas and decreased areas of glucose metabolism in three groups. We defined that 1 refers to INCREASED areas, -1, DECREASED areas and 0, just NO CHANGE. | Baseline - 2 weeks | 
| Changes in Functional Performance in Daily Activities | Pediatric Evaluation of Disability Inventory (PEDI) for assessing functional performance in daily activities in children (All values are adjusted and higher value means better functional performance, 0 - worst, 100 - best). We reported here 2 scales and 3 domains of each scale: a Functional Skill Scale (FSS) and a Caregiver Assistance Scale (CAS) which are divided respectively into 3 domains: self care, mobility, and social function. Categories of outcome table are each domain scores measured at each assessment time point. | Baseline -1 month - 3 months - 6 months | 
| Changes in Functional Independence in Daily Activities | WeeFIM (Functional Independence Measure for Children) measures functional independence in daily activities. WeeFIM contains 18 items and each item is ranked from complete dependence (scored as 1) to complete independence (scored as 7). The range is from 18 to 126 and higher scores mean more independent performance in daily activities. Categories of outcome table are total WeeFIM scores measured at each assessment time point. | Baseline - 1 month - 3 months - 6 months | 
| Changes in Muscle Strength | Summation of MMT (manual muscle strength test score): summated scores of the manual muscle strength test (zero=0, trace=1, poor=2, fair=3, good=4, normal=5) for flexors, extensors, abductors, and adductors of bilateral shoulder and hip joints; flexors and extensors of bilateral elbow, wrist, and knee; dorsiflexors and plantar flexors of the ankles (range: 0   160) Higher score means better muscle strength. Categories of outcome table are summation of MMT scores measured at each assessment time point. | Baseline - 1 month - 3 months - 6 months | 
| Changes in Hand Function | QUEST (Quality of Upper Extremity Skills Test) as a standardized measurement tool for assessing hand function consisting of sub-scales; dissociated movement, grasps, weight bearing, and protective extension. These are standardized to range from zero (or below zero in grasp section) to 100 and higher values mean better hand function. We reported QUEST differences between each assessment times. | Baseline - 1 month - 3 months - 6 months | 
| Number of Participants With Serious Adverse Events as a Measure of Safety,Which Are Related to Umbilical Cord Blood, Erythropoietin, or Immunosuppressant | The number of patients with serious adverse events within each group; Serious adverse events were defined as any event that resulted in death, was life-threatening, required hospitalization or prolonged the hospital stay, or was otherwise serious in the judgment of the investigator. | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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umbilical cord blood, stem cell, cerebral palsy