Mesenchymal Stem Cells With Cooling Therapy for Infants With Hypoxic-Ischemic Encephalopathy

Official title

Efficacy of Using Mesenchymal Stem Cells With Therapeutic Hypothermia in Infants With Perinatal Hypoxic-Ischemic Encephalopathy: A Double Blind, Randomized Controlled Trial

Overview

Hypoxic-ischemic encephalopathy (HIE) is a serious condition in newborns caused by lack of oxygen and blood flow around the time of birth. Standard treatment with cooling therapy (therapeutic hypothermia) lowers the risk of death or disability, but many infants still suffer long-term problems. This study will test whether adding stem cell therapy after cooling can further improve outcomes. The stem cells are taken from donated human placentas (Wharton's jelly-derived mesenchymal stem cells, MSCs). The cells are prepared under strict laboratory standards and checked for safety. Infants with moderate to severe HIE who have completed cooling will be randomly assigned to receive either three intravenous infusions of MSCs or placebo within the first 10 days of life. Each infusion is given over about 30 minutes while the infant is closely monitored. Researchers will follow participants for up to 2 years. The main outcome is whether MSC treatment can reduce the combined risk of death or serious developmental delay at 1 year of age. The study will also track brain MRI findings, safety events, and developmental progress at 2 years.

Detailed description

Perinatal hypoxic-ischemic encephalopathy (HIE) is a major cause of neonatal death and long-term disability worldwide. Therapeutic hypothermia (TH) is the established standard of care for term and near-term infants with moderate to severe HIE. Large randomized trials and systematic reviews have demonstrated that TH significantly reduces the combined outcome of death or major neurodevelopmental disability at 18 months of age (relative risk 0.75; 95% confidence interval 0.68-0.83). However, despite this benefit, many infants continue to have poor outcomes. Importantly, a recent meta-analysis indicated that in upper-middle-income countries, the effect of TH was smaller and did not reach statistical significance (RR 0.67; 95% confidence interval 0.41-1.09), underscoring the need for effective adjunctive treatments.

Mesenchymal stem cells (MSCs) derived from Wharton's jelly of the human umbilical cord have emerged as a promising adjunctive therapy. Preclinical studies demonstrate that MSCs exert neuroprotective and regenerative effects via anti-inflammatory, anti-apoptotic, and trophic mechanisms. Early-phase clinical studies of cord blood or MSC products in neonatal HIE have shown feasibility and acceptable safety, with signals suggesting improved neurological recovery. Nevertheless, controlled trials specifically testing MSCs after completion of TH in neonates are lacking.

This study is a pilot, randomized, double-blind, placebo-controlled trial to evaluate the feasibility, safety, and potential efficacy of repeated intravenous infusions of Wharton's jelly-derived allogeneic MSCs in neonates with moderate to severe perinatal HIE who have completed TH. Forty infants (gestational age ≥34 weeks, postnatal age ≤10 days) will be randomized in a 1:1 ratio to receive either MSCs or placebo.

The intervention group will receive three intravenous doses of MSCs (2 × 10\^6 cells/kg per dose, suspended in normal saline) administered over approximately 30 minutes. The control group will receive equivalent volumes of placebo (normal saline). Infants, parents, and treating clinicians will remain blinded to allocation.

All cell products are prepared in a GMP-compliant cleanroom facility with rigorous quality control testing, including sterility, endotoxin, mycoplasma, viability, morphology, immunophenotype, and karyotype. Donor placental tissue undergoes standard infectious disease screening.

Participants will be continuously monitored during and after infusion in the neonatal intensive care unit. Prespecified safety endpoints include fever, sepsis, hemodynamic instability, seizure control, acute liver failure, acute kidney injury, thrombosis, and death. A Data Safety Monitoring Board (DSMB) will review interim safety data at 25%, 50%, and 75% enrollment, and at 50% of 1-year follow-up. Predefined stopping rules will apply if significant safety concerns are identified.

The primary outcome is the composite of death or neurodevelopmental disability at 1 year of age, defined by Bayley Scales of Infant and Toddler Development, Fourth Edition (BSID-IV) cognitive, language, or motor scores \<70. Secondary outcomes include hospital outcomes, brain MRI at 1 month (scored by Weeke criteria), HLA antibody formation at 9-12 months, and neurodevelopmental status at 2 years.

This pilot trial is designed to establish feasibility, evaluate safety, and generate preliminary efficacy estimates to inform future multicenter trials. All infants will receive standard TH and follow-up care, with the investigational therapy given only after cooling to test whether MSCs can further reduce death or disability in this high-risk population.

Interventions

• Biological Wharton's jelly-derived mesenchymal stem cells
  MSCs (2x10\^6 cells/kg) in 10 mL 0.9%normal saline administered intravenously within 10 days, postnatally after TH completion, every 24 hours for 3 consecutive days
• Drug 0.9 % Normal Saline
  0.9% normal saline 10 mL administered intravenously within 10 days, postnatally after TH completion, every 24 hours for 3 consecutive days

Primary outcome measures

• Death or neurological disability [Time frame: At 12 months of age]

Secondary outcome measures (7)

• Death or neurological disability [Time frame: At 24 months postnatal age]
• MR-detected brain injury [Time frame: At 1 month of age]
• Severe adverse events [Time frame: From first study infusion until hospital discharge, up to 12 months]
• HLA antibody formation [Time frame: At 9-12 months of age]
• Length of birth hospitalization [Time frame: Through hospital discharge, up to 12 months]
• Incidence of infection [Time frame: Through hospital discharge, up to 12 months]
• Serum concentrations of IL-6, IL-10, and TNF-α [Time frame: Baseline (within 24 hours before administration of the first study dose), and 24 and 72 hours after completion of the three-dose treatment regimen.]

Eligibility criteria

Inclusion criteria

• Term and late-preterm infants (gestational age ≥34 weeks)
• Diagnosed with moderate to severe HIE based on modified Sarnat staging
• Received TH per standard protocol
• Parental consent obtained

Exclusion criteria

• Major congenital anomalies or genetic syndromes
• Severe sepsis or active infection
• Severe coagulopathy or bleeding disorders
• Multi-organ failure

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

Thailand · 1 center

• Siriraj Hospital, Mahidol University — Bangkok

Publications

• Xu J, Feng Z, Wang X, Xiong Y, Wang L, Ye L, Zhang H. hUC-MSCs Exert a Neuroprotective Effect via Anti-apoptotic Mechanisms in a Neonatal HIE Rat Model. Cell Transplant. 2019 Dec;28(12):1552-1559. doi: 10.1177/0963689719874769. Epub 2019 Sep 12. PMID 31512502
• Bruschettini M, Romantsik O, Moreira A, Ley D, Thebaud B. Stem cell-based interventions for the prevention of morbidity and mortality following hypoxic-ischaemic encephalopathy in newborn infants. Cochrane Database Syst Rev. 2020 Aug 19;8(8):CD013202. doi: 10.1002/14651858.CD013202.pub2. PMID 32813884
• Teo EJ, Jones LE, Wixey JA, Boyd RN, Colditz PB, Bjorkman ST. Combined hypothermia and mesenchymal stem cells in animal models of neonatal hypoxic-ischaemic encephalopathy: a systematic review. Pediatr Res. 2022 Jul;92(1):25-31. doi: 10.1038/s41390-021-01716-y. Epub 2021 Sep 4. PMID 34482377
• Ahn SY, Chang YS, Sung DK, Sung SI, Park WS. Hypothermia broadens the therapeutic time window of mesenchymal stem cell transplantation for severe neonatal hypoxic ischemic encephalopathy. Sci Rep. 2018 May 16;8(1):7665. doi: 10.1038/s41598-018-25902-x. PMID 29769612
• Terada K, Sasaki M, Nagahama H, Kataoka-Sasaki Y, Oka S, Ukai R, Yokoyama T, Iizuka Y, Sakai T, Fukumura S, Tsugawa T, Kocsis JD, Honmou O. Therapeutic efficacy of intravenous infusion of mesenchymal stem cells in rat perinatal brain injury. Pediatr Res. 2023 Dec;94(6):1921-1928. doi: 10.1038/s41390-023-02717-9. Epub 2023 Jul 8. PMID 37422495
• van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Mesenchymal stem cell treatment after neonatal hypoxic-ischemic brain injury improves behavioral outcome and induces neuronal and oligodendrocyte regeneration. Brain Behav Immun. 2010 Mar;24(3):387-93. doi: 10.1016/j.bbi.2009.10.017. Epub 2009 Oct 31. PMID 19883750
• van Velthoven CT, Kavelaars A, van Bel F, Heijnen CJ. Repeated mesenchymal stem cell treatment after neonatal hypoxia-ischemia has distinct effects on formation and maturation of new neurons and oligodendrocytes leading to restoration of damage, corticospinal motor tract activity, and sensorimotor function. J Neurosci. 2010 Jul 14;30(28):9603-11. doi: 10.1523/JNEUROSCI.1835-10.2010. PMID 20631189
• Wagenaar N, de Theije CGM, de Vries LS, Groenendaal F, Benders MJNL, Nijboer CHA. Promoting neuroregeneration after perinatal arterial ischemic stroke: neurotrophic factors and mesenchymal stem cells. Pediatr Res. 2018 Jan;83(1-2):372-384. doi: 10.1038/pr.2017.243. Epub 2017 Nov 1. PMID 28949952

Identifiers

NCT: NCT07018739 · Si 213/2025

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗