Study of hCT-MSC in Newborn Infants With Moderate or Severe HIE

Study Overview
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Brief Summary
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To determine the safety of single and repeated intravenous doses of hCT-MSC in newborn infants with HIE.

Detailed Description
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The purpose of this study is to assess the safety of one and two intravenous infusions of human umbilical cord tissue-derived mesenchymal stromal cells (hCT-MSC), the first administered in the first 48 postnatal hours, and the second at two months postnatal age, in term and near term infants with moderate to severe neonatal hypoxic-ischemic encephalopathy (HIE). This is a phase I, prospective, open-label trial designed to assess the safety of one or two intravenous doses of hCT-MSC in newborn infants with moderate to severe HIE who are recipients of therapeutic hypothermia. Infants born at 36 0/7 weeks gestation or later who have moderate to severe hypoxic-ischemic encephalopathy and are receiving therapeutic hypothermia will be eligible to participate. Investigators project an accrual of 6 patients. All infants will receive intravenous infusion(s) of hCT-MSCs. The first cohort of three infants will receive a single dose in the first 48 postnatal hours. If there are no safety concerns, the second cohort of three infants will receive two doses, with the first dose given in the first 48 postnatal hours and the second dose given approximately two months after the first dose. The potential risks associated with infusion of MSCs include a reaction to the product (rash, shortness of breath, wheezing, difficulty breathing, hypotension, swelling around the mouth, throat or eyes, tachycardia, diaphoresis), transmission of infection, and HLA sensitization. Another risk of this study is loss of confidentiality or privacy. Every effort will be made to keep the infant's medical record confidential. The results will be summarized using descriptive statistics and statistical testing as appropriate. Continuous secondary endpoints will be summarized using mean, standard deviation, CV%, median, minimum, and maximum.

Official Title
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A Phase I Study of hCT-MSC, an Umbilical Cord-Derived Mesenchymal Stromal Cell Product, in Newborn Infants With Moderate or Severe Hypoxic- Ischemic Neonatal Encephalopathy.

Conditions
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Moderate to Severe Hypoxic-ischemic Encephalopathy

Intervention / Treatment
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* Biological: Infusion of hCT-MSC


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 36 0/7th weeks gestation or older at the time of delivery. Able to receive one dose of hCT-MSCs in the first 48 postnatal hours Willingness to return for one year assessments. Signs of encephalopathy within 6 hours of age Exclusion Criteria: Major congenital or chromosomal abnormalities Severe growth restriction (birth weight <1800 g) Opinion by attending neonatologist that the study may interfere with clinical treatment or safety of subject Moribund neonates for whom no further treatment is planned Infants whose mothers have unknown serologies for Hepatitis B or HIV Infants born to mothers are known to be HIV, Hepatitis B, Hepatitis C or who have active syphilis or CMV infection in pregnancy Infants suspected of overwhelming sepsis ECMO initiated or likely in the first 48 hours of life Mother suspected to have intraamniotic infection at time of birth. ALL blood gases (cord and postnatal) done within the first 60 minutes had a pH > 7.15 AND base deficit < 10 mEq/L (source can be arterial, venous or capillary) Mother with documented Zika infection during this pregnancy Availability of autologous cord blood collected and usable in the randomized trial of autologous volume- and red blood cell-reduced cord blood cells (Duke IRB Pro00066647; clinical trials.gov link: https://clinicaltrials.gov/ct2/show/NCT02612155 )

Ages Eligible for Study
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Minimum Age: 0 Hours
Maximum Age: 48 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: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The first cohort of three patients will receive a single dose in the first 48 postnatal hours. If there are no safety concerns, the second cohort of three patients will receive two doses, with the first dose given in the first 48 postnatal hours and the second dose given approximately two months after the first dose.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First cohort of 3 subjects enrolled<br>The first cohort of three patients will receive a single dose in the first 48 postnatal hours. | Biological: Infusion of hCT-MSC<br>* Infants who meet enrollment criteria for moderate to severe hypoxic ischemic encephalopathy will receive 1 infusion of hCT-MSC within the first 48 postnatal hours. hCT-MSCs are a product of allogeneic cells manufactured from digested umbilical cord tissue that is expanded in culture, cryopreserved and banked. hCT-MSCs are manufactured from umbilical cord tissue donated to the Carolinas Cord Blood Bank, an FDA-licensed, FACT-accredited, public cord blood bank at Duke University Medical Center, after written informed consent from the baby's mother. Cord tissue is harvested from the placentas of male babies delivered by elective C-section after a normal, full- term pregnancy.<br>|
| Experimental: Second cohort of 3 subjects enrolled<br>If there are no safety concerns after the first cohort of 3 subjects are infused then the second cohort of three patients will receive two doses, with the first dose given in the first 48 postnatal hours and the second dose given approximately two months after the first dose. | Biological: Infusion of hCT-MSC<br>* Infants who meet enrollment criteria for moderate to severe hypoxic ischemic encephalopathy will receive 1 infusion of hCT-MSC within the first 48 postnatal hours. hCT-MSCs are a product of allogeneic cells manufactured from digested umbilical cord tissue that is expanded in culture, cryopreserved and banked. hCT-MSCs are manufactured from umbilical cord tissue donated to the Carolinas Cord Blood Bank, an FDA-licensed, FACT-accredited, public cord blood bank at Duke University Medical Center, after written informed consent from the baby's mother. Cord tissue is harvested from the placentas of male babies delivered by elective C-section after a normal, full- term pregnancy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of infusion reactions | for this study, infusion reactions are defined as anaphylactic or anaphylactoid reactions with clinical signs inclusive of skin rashes, bronchospasm, angioedema, myocardial infarcts, arrhythmias, and acute lung injury. | 24 hours after each infusion | 
| Incidence of Infections post-infusion | for this study, infections recorded as safety endpoints will be defined as bacterial, viral or fungal infections identified by culture or molecular methodologies within two weeks after administration of hCT-MSC. | Up to 2 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Survival | Death prior to discharge from initial hospitalization | Up to 6 months | 
| Neurodevelopmental Assessments | 1 year (12 - 16 postnatal months) Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III) assessments in cognitive, language and motor development. Moderate to Severe CP will be assigned with cognitive score ,70, motor score ,70 and with Gross Motor Function Classification System >=2. | Up to 16 postnatal months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hypoxic-ischemic encephalopathy, newborn infants, therapeutic hypothermia, hCT-MSC, an Umbilical Cord Tissue-Derived Mesenchymal Stromal Cell Product