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Hypoxic-Ischemic Encephalopathy, NeonatalPhase 1/2SiSTEM-NEONCT07018739

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

A Phase 1/2 study testing Wharton's jelly-derived mesenchymal stem cells and 0.9 % Normal Saline in people with Hypoxic-Ischemic Encephalopathy, Neonatal and Brain Injuries, Hypoxic-Ischemic, run by Mahidol University at 1 site in Thailand.

Not yet recruiting

Opening soon. The study is approved but enrolment has not started yet. Sites may already take enquiries.

Sites and contacts
Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 4 to 9 days
What is being tested?
Wharton's jelly-derived mesenchymal stem cells and 0.9 % Normal Saline
Type of treatment
Injection or infusion
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
40 participants
Where
1 siteThailand
Study dates
15 Sep 2026to Dec 2033
Phase
Phase 1/2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 4 to 9 days
  • All sexes
  • No healthy volunteers
  • Child

Who may be able to join

  • 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

Who cannot join

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

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Ratchada Kitsommart, MD contact

66961715544

ratchada.kit@mahidol.ac.th

Buranee Yangthara, MD, PhD contact

66843270809

buraneeyangthara@gmail.com

Thailand1 site

  • Siriraj Hospital, Mahidol University

    Bangkok, 10700

    Ratchada Kitsommart, MD, 66961715544, ratchada.kit@mahidol.ac.th

Other trials in Thailand

About this study

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

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.

Read more

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.

Read the 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.

Being tested
Wharton's jelly-derived mesenchymal stem cells, 0.9 % Normal Saline
Keywords
Perinatal HIE, Mesenchymal stem cells, Wharton&amp;#39;s jelly, therapeutic hypothermia
Medical subject headings
Hypoxia-Ischemia, Brain, Brain Injuries

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Wharton's jelly-derived mesenchymal stem cellsBiological

    Also called 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 SalineDrug

    Also called 0.9%NSS

    0.9% normal saline 10 mL administered intravenously within 10 days, postnatally after TH completion, every 24 hours for 3 consecutive days

Study groups in NCT07018739
Study groupRoleWhat they receive
Wharton's jelly-derived mesenchymal stem cellsExperimentalA 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.
Receives: Biological: Wharton's jelly-derived mesenchymal stem cells
PlaceboPlacebo comparatorA 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.
Receives: Drug: 0.9 % Normal Saline

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Death or neurological disability

    Including any causes of deaths. Neurological disability is defined by Bayley Scales of Infant Development-IV <70 (ranging from 40 to 160, with higher scores indicating better neurodevelopmental outcomes)

    Measured: At 12 months of age

Secondary outcomes (7)

  1. Death or neurological disability

    Any causes of death. Neurological disability is defined as Bayley Scales of Infant Development-IV <70 (ranging from 40 to 160, with higher scores indicating better neurodevelopmental outcomes)

    Measured: At 24 months postnatal age

  2. MR-detected brain injury

    Brain injury detected by Weeke MRI score on brain MRI (total score range 0-57; higher scores indicate worse outcomes).

    Measured: At 1 month of age

  3. Severe adverse events

    One of these adverse events occurring after drug initiation:

    Hemodynamic instability (persistent HR >180 beats per minute, BP <5th %tile for gestational age and postnatal age, require new treatment (volume resuscitation/inotropic agents/vasopressor agents) Acute liver failure (new-onset of hyperbilirubinemia with INR ≥3 with no response to vitamin K administration) Thrombosis (any events such as renal vein thrombosis, stroke) Death before discharge

    Measured: From first study infusion until hospital discharge, up to 12 months

  4. HLA antibody formation

    Presence of anti-HLA antibodies assessed by panel-reactive antibody (PRA) testing.

    Measured: At 9-12 months of age

  5. Length of birth hospitalization

    Total days from birth to hospital discharge.

    Measured: Through hospital discharge, up to 12 months

  6. Incidence of infection

    Culture-proven infection requiring antimicrobial therapy.

    Measured: Through hospital discharge, up to 12 months

  7. Serum concentrations of IL-6, IL-10, and TNF-α

    Serum concentrations of IL-6, IL-10, and TNF-α will be measured from 1 mL blood samples collected at baseline (within 24 hours before administration of the first study dose) and at 24 and 72 hours after completion of the three-dose study treatment. Changes in biomarker concentrations over time will be compared between treatment groups.

    Measured: Baseline (within 24 hours before administration of the first study dose), and 24 and 72 hours after completion of the three-dose treatment regimen.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Jun 2025
  2. Study start15 Sep 2026 (estimated)
  3. Primary completionDec 2032 (estimated)
  4. Study completionDec 2033 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
40 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT07018739
Sponsor's protocol ID
Si 213/2025
Acronym
SiSTEM-NEO
Status last verified
Aug 2026
First submitted
4 Jun 2025
Last updated
2 Sep 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Yes: De-identified individual participant data underlying published results (e.g., baseline demographics, adverse events, primary and secondary outcomes including Bayley-IV scores and Weeke MRI scores).

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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 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.

    PubMed 28949952

  • 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.

    PubMed 27535166

  • 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.

    PubMed 23133515

  • 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.

    PubMed 38902120

  • 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.

    PubMed 15199405

  • 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.

    PubMed 19172693

  • 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.

    PubMed 27632779

  • 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.

    PubMed 33362471

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Wharton's jelly-derived mesenchymal stem cells and 0.9 % Normal Saline in people with Hypoxic-Ischemic Encephalopathy, Neonatal and Brain Injuries, Hypoxic-Ischemic, run by Mahidol University at 1 site in Thailand.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: opening soon, as of the sponsor's last update on 2 Sep 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Thailand. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

Contact Ratchada Kitsommart, MD (66961715544, ratchada.kit@mahidol.ac.th), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Death or neurological disability (time frame: At 12 months of age). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT07018739, which also lists 16 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Sep 2026.

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