A Randomized Study of Autologous Umbilical Cord Blood Reinfusion in Children With Cerebral Palsy

Study Overview
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Brief Summary
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The purpose of this study is to determine the efficacy of a single intravenous infusion of autologous umbilical cord blood (UCB) for the treatment of pediatric patients with spastic cerebral palsy.

Detailed Description
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Cerebral palsy results from in utero or perinatal injury to the developing brain, often through stroke, hypoxic insult or hemorrhage. Currently available treatments for patients with cerebral palsy are supportive, but not curative. Umbilical cord blood (UCB) has been shown to lessen the clinical and radiographic impact of hypoxic brain injury and stroke in animal models. UCB also engrafts and differentiates in brain, facilitating neural cell repair, in animal models and human patients with inborn errors of metabolism undergoing allogeneic, unrelated donor UCB transplantation. We hypothesize that, in the setting of brain injury, infusion of autologous UCB will facilitate neural cell repair resulting in improved function in pediatric patients with cerebral palsy.

Official Title
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Is Autologous Umbilical Cord Blood Reinfusion Beneficial in Children With Cerebral Palsy: A Randomized, Blinded, Placebo-Controlled, Crossover Study

Conditions
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CP, Cerebral Palsy, Spastic Cerebral Palsy

Intervention / Treatment
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* Biological: Autologous UCB Reinfusion
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 12 months and ≤ 6 years Diagnosis: Spastic cerebral palsy with diplegia, hemiplegia, or quadraplegia. Performance status: Gross Motor Function (GMF) Classification Score levels II - IV or GMF Score leve I, age >/= 2 years Spastic hemiplegia: GMF Score II-IV or minimal functional capabilities in the affected upper extremity. A subject classified as GMFCS level I with significant upper extremity impairment will be eligible if the affected upper extremity is used as an assist only. An eligibility committee will meet to review the child's records and determine eligibility. Bilateral hypotonic CP (diplegia or quadriplegia): GMF Score II-IV and an abnormal brain MRI suggestive of an acquired etiology (versus a genetic etiology or brain malformation). Autologous umbilical cord blood available at a private or public cord blood bank with a minimum total nucleated cell dose of ≥ 1 x 107 cells/kilogram. Parental consent. Exclusion Criteria: Athetoid cerebral palsy. Autism and autistic spectrum disorders without motor disability. Hypsarrhythmia. Intractable seizures causing epileptic encephalopathy. Evidence of a progressive neurologic disease. Known HIV or uncontrolled bacterial, fungal, or viral infections. Impaired renal or liver function as determined by serum creatinine >1.5mg/dL and/or total bilirubin >1.3mg/dL. Head circumference >3 standard deviations below the mean for age. Known genetic disease or phenotypic evidence of a genetic disease on physical examination. Concurrent genetic or acquired disease or comorbidity(ies) that could require a future allogeneic stem cell transplant. Requires ventilatory support, including home ventilator, CPAP, BiPAP, or supplemental oxygen. Patient's medical condition does not permit safe travel. Previously received any form of cellular therapy. Autologous umbilical cord blood unit has any of the following: Total nuclear cell dose < 1 x 107 cells/kilogram Positive maternal infectious disease markers (except CMV) Evidence of infectious contamination of the cord blood unit Lack of a test sample to confirm identity Evidence of a genetic disease Unable to obtain parental consent.

Ages Eligible for Study
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Minimum Age: 12 Months
Maximum Age: 6 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: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Autologous UCB Reinfusion First,Then Placebo<br>Subjects receive their autologous umbilical cord blood cells at Baseline, than placebo at Year 1. | Biological: Autologous UCB Reinfusion<br>* Autologous umbilical cord blood (UCB) reinfusion<br>Other: Placebo<br>* Placebo<br>|
| Placebo Comparator: Placebo First, Then Autologous UCB Reinfusion<br>Subjects receive placebo at Baseline, then autologous umbilical cord blood cell reinfusion at Year 1. | Biological: Autologous UCB Reinfusion<br>* Autologous umbilical cord blood (UCB) reinfusion<br>Other: Placebo<br>* Placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Gross Motor Function Measure 66 (GMFM-66) Score | Change in Gross Motor Function Measure 66 (GMFM-66) Score from Baseline to Year 1. The GMFM-66 is a clinical tool used to evaluate gross motor function in children with cerebral palsy and is scored using a propriety software program called the Gross Motor Ability Estimator (GMAE) that produces an interval level continuous score ranging from 0 to 100. Higher scores indicate better motor function. A negative change in GMFM-66 score indicates a reduction in motor function, a positive change indicates improvement in motor function, and zero indicates no change in motor function. | Baseline to Year 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Peabody Gross Motor Quotient From Baseline to Year 1 | The Peabody Developmental Motor Scales - Second Edition (PDMS-2) measures gross and fine motor skills in children from birth through five years of age. The Gross Motor Quotient score from the PDMS-2 was used in this study to evaluate gross motor function. The Gross Motor Quotient measures the ability to use large muscle systems for locomotion, maintain a stable posture when not moving, and throw/catch objects. The range of possible scores is 41 to 164. High scores indicate better gross motor function. Lower scores indicate less gross motor function ability. The change in Gross Motor Quotient from Baseline to Year 1 was evaluated in this study. Positive numbers indicate an increase in gross motor ability, negative numbers indicate decreases in gross motor function, and a zero indicates no change. | Baseline to Year 1 | 
| Change in IT-QOL Questionnaire Score | The Infant and Toddler Quality of Life Questionnaire (IT-QOL) was utilized for children ages one to three years at study entry.This 97-item questionnaire is completed by the parents and covers 12 concepts related to the physical, mental, and social well being of the child and the impact of their illness on the family. Scores range from 0 (worst health) to 100 (best health). The change from Baseline to Year 1 is summarized here for each of the 12 items on the questionnaire. Negative values indicate a decline in quality of life over time, positive values indicate an improvement, and zero indicates no change. | Baseline to Year 1 | 
| Change in CP-QOL Score | Children age four years or older at study entry were assessed using the disease-specific CP-QOL Child assessment tool as completed by a parent. The CP-QOL Child primary-caregiver proxy form is designed for children 4 - 12 with cerebral palsy and contains 66 items which assess physical, emotional, and social well being as well as access to services and acceptance by others. Scores are summarized in seven topic areas. Scores in each area range from 0 (worst health) to 100 (best health). The change score from Baseline to Year 1 is summarized here for each item. Negative scores indicated a decrease in quality of life, positive scores indicate an increase and zero indicates no change. | Baseline, Year 1 | 
| Change in Whole Brain Connectivity Measured by Diffusion Tensor Magnetic Resonance Imaging (MRI) | Change in number of connections in the brain as measured by diffusion tensor magnetic resonance imaging (MRI). Changes in connectivity are normalized to white matter volume of the brain. A positive number indicates an increase in connections, a negative number indicates a decrease, and zero indicates no change. The number of connections is expressed in terms of 10e5. For example, a change of 1 indicates an increase of 1x10e5 or 100,000 connections. | Baseline to Year 1 | 
| Change in Loes Score of Functional MRI From Baseline to Year 1 and From Year 1 to Year 2 | No data were collected from this procedure because enrolled subjects who were eligible to receive fMRI were unable to comply with the procedure. | Baseline, Year 1, Year 2 | 
| Change in Bayley Scales of Infant and Toddler Development-III, Cognitive Composite From Baseline to Year 1 | Cognitive function was assessed in English-speaking study participants using one of three different tools depending on the age of the patient at the time of assessment: The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), the Wechsler Intelligence Scale for Children (WISC-IV), and the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Some patients were assessed with different tools at subsequent visits as they aged during the conduct of the trial. The Bayley-III is designed to assess developmental functioning of infants and toddlers. Scores for the Cognitive Composite range from 1 to 19 and results in the range of 8 to 12 are considered average. The outcome measure reported here is the change in Cognitive Composite between Baseline to Year 1. Positive numbers indicate increases in cognitive functioning, negative numbers indicate a decrease, and zero indicates no change. | Baseline to Year 1 | 
| Change in Wechsler Preschool and Primary Scale of Intelligence (WPPSI) III Full Scale Intelligence Quotient (IQ) for Younger Children (Ages 2 Years & 6 Months to 3 Years & 11 Months) From Baseline to Year 1. | Cognitive function was assessed in English-speaking study participants using one of three different tools depending on the age of the patient at the time of assessment: The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), the Wechsler Intelligence Scale for Children (WISC-IV), and the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Some patients were assessed with different tools at subsequent visits as they aged during the conduct of the trial. There are two versions of the WPPSI-III for two different age ranges: 2 years & 6 months to 3 years & 11 months, and 4 years to 7 years & 3 months. The Full Scale IQ is calculated for both age ranges and provides a continuous score with an average of 100 and a standard deviation of 15. Change from Baseline to Year 1 was evaluated, with positive numbers indicating an increase in cognitive ability, negative numbers indicating a decrease in cognitive ability, and zero indicating no change. | Baseline to Year 1 | 
| Change in the Wechsler Intelligence Scale for Children (WISC-IV) From Baseline to Year 1. | Cognitive function was assessed in English-speaking study participants using one of three different tools depending on the age of the patient at the time of assessment: The Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), the Wechsler Intelligence Scale for Children (WISC-IV), and the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Some patients were assessed with different tools at subsequent visits as they aged during the conduct of the trial. The WISC-IV is designed for children 6 years 0 months to 16 years 11 months. This study used the Full Scale IQ, which ranges from 45 to 155 with a mean of 100 and standard deviation of 15. Higher scores indicate stronger cognitive function. Scores between 90 and 110 are considered to be within the range of average IQ. | Baseline to Year 1 | 
| Change in Cognitive Z-Score From Baseline to Year 1 | Because patients in this study were evaluated with different cognitive assessments based on their age at the time of assessment (The Bayley-III Cognitive Composite, the WPSSI-III Full Scale IQ, and the WISC-IV Full Scale IQ Composite), with some patients being assessed using different tools at subsequent visits during the trial, a method for combining the assessments was employed to evaluate change in cognitive function over time in as many patients as possible. A cognitive Z-score was calculated for each participant at Baseline and Year 1 by adjusting each score by the relevant assessments' population mean and standard deviation. The Z-scores represent the distance from the population mean, as measured by standard deviations. The analysis presented here summarizes the change in Z-score between Baseline and Year 1. A positive number indicates an increase in cognitive function, a negative number indicates a decrease, and zero indicates no change. | Baseline to Year 1 | 
| Change in Assisting Hand Assessment (AHA) Score From Baseline to Year 1 | The Assisting Hand Assessment (AHA) measures the use of hemiplegic cerebral palsy patients' involved hand in tasks involving two hands. The test is valid for ages 18 months to 12 years. The score is an interval scale ranging from 22 to 88 with higher numbers indicating more effective use of the affected hand in performance of bimanual tasks. Change in this score was evaluate between Baseline and Year 1. Positive numbers indicate more effective use of the affected hand, negative numbers indicate a reduction in the effective use of the affected hand, and a zero indicates no change. | Baseline to Year 1 | 
| Change in Pediatric Evaluation of Disability (PEDI) Self Care Score | The Pediatric Evaluation of Disability is used to evaluate functional skills in children aged 6 months to 7 years in three areas: Self Care, Mobility, and Social Function. The score in each area can range from 10-90. Higher scores indicate higher function. The change from Baseline to Year 1 in the Self Care score is presented here. Positive scores indicate increased function, negative scores indicate a decrease, and zero indicates no change. | Baseline to Year 1 | 
| Change in Pediatric Evaluation of Disability (PEDI) Mobility Score | The Pediatric Evaluation of Disability is used to evaluate functional skills in children aged 6 months to 7 years in three areas: Self Care, Mobility, and Social Function. The score in each area can range from 10-90. Higher scores indicate higher function. The change from Baseline to Year 1 in the Mobility score is presented here. Positive scores indicate increased function, negative scores indicate a decrease, and zero indicates no change. | Baseline to Year 1 | 
| Change in Pediatric Evaluation of Disability (PEDI) Social Function Score | The Pediatric Evaluation of Disability is used to evaluate functional skills in children aged 6 months to 7 years in three areas: Self Care, Mobility, and Social Function. The score in each area can range from 10-90. Higher scores indicate higher function. The change from Baseline to Year 1 in the Social Function score is presented here. Positive scores indicate increased function, negative scores indicate a decrease, and zero indicates no change. | Baseline to Year 1 | 
| Change in Child Behavior Checklist (CBCL) Z-score Internalizing Problems From Baseline to Year 1 | Two versions of the CBCL exist for children ages 1.5 to 5 years and ages 6-18 years. The CBCL evaluates internalizing and externalizing behaviors and total problems using 99-item assessments that are scored on an ordinal scale as 0 for not true of the child, 1 for somewhat or sometimes true of the child, and 2 for very true or often true of the child based on behavior in the preceding two months. Scores are expressed on a standard normal distribution with mean 50 and standard deviation 10. Z scores were created for analysis. A Z-score represents the distance from the population mean in terms of the number of standard deviations. The change in Z-score from Baseline to Year 1 was calculated for each patient. A positive number indicates an increase in the behavior, a negative number indicates a decrease in the behavior, and a zero indicates no change. | Baseline to Year 1 | 
| Change in Child Behavior Checklist (CBCL) Z-score Externalizing Problems From Baseline to Year 1 | Two versions of the CBCL exist for children ages 1.5 to 5 years and ages 6-18 years. The CBCL evaluates internalizing and externalizing behaviors and total problems using 99-item assessments that are scored on an ordinal scale as 0 for not true of the child, 1 for somewhat or sometimes true of the child, and 2 for very true or often true of the child based on behavior in the preceding two months. Scores are expressed on a standard normal distribution with mean 50 and standard deviation 10. Z scores were created for analysis. A Z-score represents the distance from the population mean in terms of the number of standard deviations. The change in Z-score from Baseline to Year 1 was calculated for each patient. A positive number indicates an increase in the behavior, a negative number indicates a decrease in the behavior, and a zero indicates no change. | Baseline to Year 1 | 
| Change in Child Behavior Checklist (CBCL) Z-score Total Problems From Baseline to Year 1 | Two versions of the CBCL exist for children ages 1.5 to 5 years and ages 6-18 years. The CBCL evaluates internalizing and externalizing behaviors and total problems using 99-item assessments that are scored on an ordinal scale as 0 for not true of the child, 1 for somewhat or sometimes true of the child, and 2 for very true or often true of the child based on behavior in the preceding two months. Scores are expressed on a standard normal distribution with mean 50 and standard deviation 10. Z scores were created for analysis. A Z-score represents the distance from the population mean in terms of the number of standard deviations. The change in Z-score from Baseline to Year 1 was calculated for each patient. A positive number indicates an increase in the behavior, a negative number indicates a decrease in the behavior, and a zero indicates no change. | Baseline to Year 1 | 
| Change in Parental Distress From Baseline to Year 1 | Parent stress was evaluated with the Parenting Stress Index - Short Form for children aged 0-12 years, which measures stress in three domains: Parental Distress, Parent-Child Dysfunctional Interaction, and Difficult Child. Results in each domain are expressed as percentiles. Scores from the 15th-80th percentile are considered to be within the normal range. Scores at or above the 85th percentile considered high distress. Scores greater than the 89th percentile indicate clinically significant levels of distress. Analysis focused on changes in percentile scores between Baseline and Year 1. Positive numbers represent an increase in distress, negative numbers represent a decrease in distress, and zero indicates no change. | Baseline to Year 1 | 
| Change in Parent-Child Dysfunctional Interaction From Baseline to Year 1 | Parent stress was evaluated with the Parenting Stress Index - Short Form for children aged 0-12 years, which measures stress in three domains: Parental Distress, Parent-Child Dysfunctional Interaction, and Difficult Child. Results in each domain are expressed as percentiles. Scores from the 15th-80th percentile are considered to be within the normal range. Scores at or above the 85th percentile considered high distress. Scores greater than the 89th percentile indicate clinically significant levels of distress. Analysis focused on changes in percentile scores between Baseline and Year 1. Positive numbers represent an increase in distress, negative numbers represent a decrease in distress, and zero indicates no change. | Baseline to Year 1 | 
| Change in Difficult Child Score From Baseline to Year 1 | Parent stress was evaluated with the Parenting Stress Index - Short Form for children aged 0-12 years, which measures stress in three domains: Parental Distress, Parent-Child Dysfunctional Interaction, and Difficult Child. Results in each domain are expressed as percentiles. Scores from the 15th-80th percentile are considered to be within the normal range. Scores at or above the 85th percentile considered high distress. Scores greater than the 89th percentile indicate clinically significant levels of distress. Analysis focused on changes in percentile scores between Baseline and Year 1. Positive numbers represent an increase in distress, negative numbers represent a decrease in distress, and zero indicates no change. | Baseline to Year 1 | 
| Modified Ashworth Scale at Baseline | The Modified Ashworth Scale uses a 6 point scale (range 0, 1, 1+, 2, 3, or 4) to measure spasticity in 5 body regions (central, right upper extremity, left upper extremity, right lower extremity, and left lower extremity). Scores of 0 indicate no increase in muscle tone whereas a score of 4 indicates rigidity in flexion or extension. | Baseline | 
| Modified Ashworth Scale at Year 1 | The Modified Ashworth Scale uses a 6 point scale (range 0, 1, 1+, 2, 3, or 4) to measure spasticity in 5 body regions (central, right upper extremity, left upper extremity, right lower extremity, and left lower extremity). Scores of 0 indicate no increase in muscle tone whereas a score of 4 indicates rigidity in flexion or extension. | Year 1 | 
| Change in Bruininks-Oseretsky-2 Total Motor Composite From Baseline to Year 1 | The Bruininks-Oseretsky Test of Motor Proficiency, Second Edition, (BOT-2) evaluates motor function in four areas: stability, mobility, strength, coordination, and object manipulation. A Total Motor Composite is then calculated and expressed on a normal distribution with mean 50 and standard deviation of 10. Higher scores indicate better motor function. The BOT-2 Total Motor Composite was used to measure motor function in children at age 6 in this study. The study intended to evaluate change in the BOT-2 Total Motor Composite from Baseline to Year 1, where positive change indicates improvement in motor function, negative change indicates decrease in motor function, and zero indicates no change. | Baseline to Year 1 | 
| Correlation Between Clinical Response and RNA Expression of Neural, Endothelial and Inflammatory Cytokines Measured by RNA Arrays in Cord Blood Cells Given to These Patients. | Various pre-selected neural, angiogenic, and anti-inflammatory markers expressed by UCB cells and clinical response will be evaluated. | 2 years | 
| Parent Experience of Child Illness (PECI) | The PECI is a 25-item measure designed to examine parental adjustment related to caring for a chronically ill child. | Baseline to Year 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cerebral Palsy, CP, Spastic Cerebral Palsy, Cord Blood, Umbilical Cord Blood, Autologous Cord Blood