Mesenchymal Stem Cells With Cooling Therapy for Infants With Hypoxic-Ischemic Encephalopathy
NCT ID: NCT07018739
Last Updated: 2025-11-19
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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NOT_YET_RECRUITING
PHASE1/PHASE2
40 participants
INTERVENTIONAL
2026-06-30
2033-12-31
Brief Summary
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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.
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Detailed Description
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
QUADRUPLE
Study Groups
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Wharton's jelly-derived mesenchymal stem cells
A total of three IV infusions of MSCs will be administered, one dose per day for three consecutive days, starting within the first 10 days of life, following the completion of TH.
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
Placebo
A total of three IV infusions of 0.9%NSS will be administered, one dose per day for three consecutive days, starting within the first 10 days of life, following the completion of TH.
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
Interventions
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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
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
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* Diagnosed with moderate to severe HIE based on modified Sarnat staging
* Received TH per standard protocol
* Parental consent obtained
Exclusion Criteria
* Severe sepsis or active infection
* Severe coagulopathy or bleeding disorders
* Multi-organ failure
4 Days
9 Days
ALL
No
Sponsors
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Siriraj Hospital
OTHER
Mahidol University
OTHER
Responsible Party
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Principal Investigators
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Ratchada Kitsommart, MD
Role: PRINCIPAL_INVESTIGATOR
Mahidol University
Locations
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Siriraj Hospital, Mahidol University
Bangkok, , Thailand
Countries
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Central Contacts
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Facility Contacts
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References
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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.
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.
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.
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.
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.
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.
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.
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.
Ahn SY, Chang YS, Sung DK, Sung SI, Ahn JY, Park WS. Pivotal Role of Brain-Derived Neurotrophic Factor Secreted by Mesenchymal Stem Cells in Severe Intraventricular Hemorrhage in Newborn Rats. Cell Transplant. 2017 Jan 24;26(1):145-156. doi: 10.3727/096368916X692861. Epub 2016 Aug 16.
Lalu MM, McIntyre L, Pugliese C, Fergusson D, Winston BW, Marshall JC, Granton J, Stewart DJ; Canadian Critical Care Trials Group. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS One. 2012;7(10):e47559. doi: 10.1371/journal.pone.0047559. Epub 2012 Oct 25.
Mintoft A, Vallatos A, Robertson NJ. Mesenchymal Stromal Cell therapy for Hypoxic Ischemic Encephalopathy: Future directions for combination therapy with hypothermia and/or melatonin. Semin Perinatol. 2024 Aug;48(5):151929. doi: 10.1016/j.semperi.2024.151929. Epub 2024 Jun 13.
Dezawa M, Kanno H, Hoshino M, Cho H, Matsumoto N, Itokazu Y, Tajima N, Yamada H, Sawada H, Ishikawa H, Mimura T, Kitada M, Suzuki Y, Ide C. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest. 2004 Jun;113(12):1701-10. doi: 10.1172/JCI20935.
Uccelli A, Moretta L, Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol. 2008 Sep;8(9):726-36. doi: 10.1038/nri2395.
Braccioli L, Heijnen CJ, Coffer PJ, Nijboer CH. Delayed administration of neural stem cells after hypoxia-ischemia reduces sensorimotor deficits, cerebral lesion size, and neuroinflammation in neonatal mice. Pediatr Res. 2017 Jan;81(1-1):127-135. doi: 10.1038/pr.2016.172. Epub 2016 Sep 15.
Kaminski N, Koster C, Mouloud Y, Borger V, Felderhoff-Muser U, Bendix I, Giebel B, Herz J. Mesenchymal Stromal Cell-Derived Extracellular Vesicles Reduce Neuroinflammation, Promote Neural Cell Proliferation and Improve Oligodendrocyte Maturation in Neonatal Hypoxic-Ischemic Brain Injury. Front Cell Neurosci. 2020 Dec 10;14:601176. doi: 10.3389/fncel.2020.601176. eCollection 2020.
Nabetani M, Shintaku H, Hamazaki T. Future perspectives of cell therapy for neonatal hypoxic-ischemic encephalopathy. Pediatr Res. 2018 Jan;83(1-2):356-363. doi: 10.1038/pr.2017.260. Epub 2017 Nov 8.
Other Identifiers
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Si 213/2025
Identifier Type: -
Identifier Source: org_study_id
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