Neuroprotective Effect of Autologous Cord Blood Combined With Therapeutic Hypothermia Following Neonatal Encephalopathy

Study Overview
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Brief Summary
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This study examines the effect of cord blood in the treatment of newborn infants with neonatal encephalopathy in combination with hypothermia, which is the standard treatment for this condition. The hypothesis is that the cord blood + hypothermia combination will produce better neuroprotection than the standard treatment of hypothermia alone.

Detailed Description
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The primary aim of this study is to determine the neuroprotective effect of intravenous administration of autologous cord blood in neonates with severe encephalopathy (hypoxic ischemic encephalopathy or cerebral infarction). It is hypothesized that the administration of autologous cord blood will be safe and well tolerated in neonates with severe encephalopathy. If a neonate is born with signs of moderate to severe encephalopathy and cooled for the encephalopathy, the neonate will receive their own cord blood. The cord blood cells are divided into 3 doses and infused at 24, 48, and 72 hours after the birth. Infants will be randomised to treatment with autologous cord blood and hypothermia or hypothermia only and followed for safety and neurodevelopmental outcome up to 18 months. All infants in both groups will be treated with hypothermia for 72 hours started within 6 hours of delivery and infants who allocated to hypothermia and xenon will also receive autologous cord blood in 24 hours from birth through a purpose designed delivery system. Additionally, postnatal neuro-developmental outcomes in neonates with encephalopathy after autologous cord blood therapy will be measured; HIE injury to the neonate/infant brain post autologous cord blood therapy by imaging will be characterized; MRI's will be obtained per clinical routine; serum levels of selected cytokine and neurotrophic factors in neonates with HIE before and after autologous cord blood therapy will be compared and immune cell phenotype and function in neonates with HIE before and after autologous cord blood therapy will be compared.

Official Title
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A Multi-Centre Safety and Efficacy Study of Autologous Cord Blood Combined With Therapeutic Hypothermia Following Neonates Encephalopathy in China

Conditions
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Hypoxic Ischemic Encephalopathy, Cerebral Infarction

Intervention / Treatment
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* Drug: Autologous cord blood
* Device: Hypothermia


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Gestational age ≥ 34 weeks Birth weight ≥ 1800 grams 10-minute Apgar score ≤5 or continued need for ventilation or severe acidosis, defined as pH <7.0 Moderate to severe encephalopathy (Sarnat II to III) A moderately or severely abnormal background aEEG voltage, or seizures identified by aEEG, if monitored Up to 24 hours of age Autologous umbilical cord blood available to infuse 3 doses within 72 hours after birth Parental informed consent Exclusion Criteria: Known major congenital anomalies, such as chromosomal anomalies, heart diseases Major intracranial hemorrhage identified by brain ultrasonography or computed tomography Severe intrauterine growth restriction (weight <1800g) Severe infectious disease, such as sepsis Inability to enroll by 24 hours of age Volume of collected cord blood <40 ml Infants in extremis for whom no additional intensive therapy will be offered by attending neonatologist Parents refuse consent

Ages Eligible for Study
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Maximum Age: 24 Hours

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cord blood with hypothermia<br>Autologous cord blood will be collected after birth and stored in Cord Blood Bank of hospital. All cord blood samples are routinely performed by dedicated, trained UCB collection staff and is restricted to deliveries of mothers who have given prior written informed consent for collection. If the mother delivered a baby with signs of HIE or cerebral infarction, Bank staff collected UCB utilizing standard procedures. Collected UCB was transported at roomtemperature in validated shippers to the NICU. Infusions were started when cells and study staff were available for administration and monitoring. Infants received up to 3 infusions, with the first dose as soon as possible after birth, and at, 48, and 72 postnatal hours. At the same time, babies will referred to neonatal intensive care unit for hypothermia therapy of cooling to 33.5 ℃ body temperature for 72 hours and standard intensive care. | Drug: Autologous cord blood<br>* Autologous cord blood will be collected after birth and administered in divided aliquots during the first 3 days of life. At the same time, babies will referred to neonatal intensive care unit for hypothermia therapy of cooling to 33.5 ℃ body temperature for 72 hours and standard intensive care.<br>|
| Active Comparator: Hypothermia<br>Hypothermia therapy of cooling to 33.5 ℃ body temperature for 72 hours and standard intensive care. | Device: Hypothermia<br>* Hypothermia therapy of cooling to 33.5 ℃ body temperature for 72 hours and standard intensive care.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mortality | The relative frequency of deaths in each group. | From birth to the age of 18 months | 
| Disability Rate | Disability, defined as a physical or mental handicap, especially one that prevents a person from living a full, normal life or from holding a gainful job. | From birth to the age of 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Neurodevelopment(Bayley Scores) | Efficacy of levetiracetam by assessment of the change from baseline to 12 months in neurodevelopment via Bayley Scores of Infant Development Mental Development Index (BSID). | At the age of 12 months | 
| Neurodevelopment(Bayley Scores) | Efficacy of levetiracetam by assessment of the change from baseline to 18 months in neurodevelopment via Bayley Scores of Infant Development Mental Development Index (BSID). | At the age of 18 months | 
| Brain Structural Alterations(MRI) | Efficacy of cord blood by assessment of the changes in brain from baseline in MRI on Day 7. | At the age of 7 days | 
| Brain Structural Alterations(MRI) | Efficacy of cord blood by assessment of the changes in brain from baseline in MRI on Day 28. | At the age of 28 days | 
| Brain Structural Alterations(MRI) | Efficacy of cord blood by assessment of the changes in brain from baseline in MRI on 12 months old. | At the age of 12 months | 
| Brain Parenchyma Alterations(MRI) | Efficacy of cord blood by assessment of the changes in brain from baseline in MRI on Day 7. | At the age of 7 Days | 
| Brain Parenchyma Alterations(MRI) | Efficacy of cord blood by assessment of the changes in brain from baseline in MRI on Day 28. | At the age of 28 days | 
| Brain Parenchyma Alterations(MRI) | Efficacy of cord blood by assessment of the changes in brain from baseline in MRI on 12 months old. | At the age of 12 months | 
| Intracranial Hemorrhage(MRI) | Efficacy of cord blood by assessment of the changes in brain from baseline in MRI on Day 7. | At the age of 7 days | 
| Intracranial Hemorrhage(MRI) | Efficacy of cord blood by assessment of the changes in brain from baseline in MRI on Day 7. | At the age of Day 28 | 
| Intracranial Hemorrhage(MRI) | Efficacy of cord blood by assessment of the changes in brain from baseline in MRI on 12 months. | At the age of 12 months | 
| Number of Adverse Events | This is a composition of general appearance includes abdomen, skin, head and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems. | In 72 hours | 
| Number of Adverse Events(Blood Pressure) | This is a composition of general appearance, blood pressure, pulse, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems. | In 72 hours | 
| Number of Adverse Events(Pulse) | This is a composition of general appearance, blood pressure, pulse, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems. | In 72 hours | 
| Number of Adverse Events(Respiratory) | This is a composition of general appearance, blood pressure, pulse, respiratory, cardiovascular, abdomen, skin, head and neck (including ears, eyes, nose, and throat), lymph nodes, thyroid, musculoskeletal and neurological systems. | In 72 hours | 
| Incidence of Complication | To gain the incidence of Polycythemia, neutropenia, thrombocytopenia, hypertension, sepsis, intraventricular hemorrhage(IVH), periventricular leukomalacia(PVL), seizure, necrotizing enterocolitis (NEC), persistent ductus arterious (PDA), apnea of prematurity, pulmonary haemorrhage, pulmonary hypertension, Prolonged blood coagulation time, retinopathy of prematurity(ROP), cardiac arrhythmia, major venous thrombosis, Renal failure treated with dialysis, pneumonia, pulmonary airleak and chronic lung disease. | From birth to the age of 28 days in each treatment period | 
| SDF-1 in Serum | Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy for hypoxic ischemic encephalopathy or cerebral infarction. | At the age of 4 days | 
| SDF-1 in Serum | Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy for hypoxic ischemic encephalopathy or cerebral infarction. | At the age of 14 days | 
| TNF-alpha in Serum | Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy for hypoxic ischemic encephalopathy or cerebral infarction. | At the age of 4 days | 
| TNF-alpha in Serum | Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy for hypoxic ischemic encephalopathy or cerebral infarction. | At the age of 14 days | 
| IL-1 in Serum | Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy for hypoxic ischemic encephalopathy or cerebral infarction. | At the age of 4 days | 
| IL-1 in Serum | Biomarkers for Oxidative Stress, Inflammation and immune response as a measure of efficacy for hypoxic ischemic encephalopathy or cerebral infarction. | At the age of 14 days |