Efficacy of Using Mesenchymal Stem Cells With Therapeutic Hypothermia in Infants With Perinatal Hypoxic-Ischemic Encephalopathy: A Double Blind, Randomized Controlled Trial
| Registry | NCT07018739, acronym SiSTEM-NEO |
|---|---|
| Status | Not yet recruiting |
| Phase | Phase 1 / Phase 2 |
| Study type | Interventional; randomized, parallel, masking: quadruple, treatment |
| Enrollment | 40 (Estimated) |
| Sponsor | Mahidol University (Other); collaborators: Siriraj Hospital |
| Conditions | Hypoxic-Ischemic Encephalopathy, Neonatal, Brain Injuries, Hypoxic-Ischemic |
| Interventions | Wharton's jelly-derived mesenchymal stem cells, 0.9 % Normal Saline (Biological, drug) |
| Dates | start 2026-09-15 (estimated), primary completion 2032-12-01 (estimated), completion 2033-12-01 (estimated), first posted 2025-06-12, last updated 2026-09-02 |
| Locations | 1 site in Thailand |
Related Papers Related Patents Related Grants Related Experts
All trials for Hypoxic-Ischemic Encephalopathy, Neonatal All trials for Brain Injuries, Hypoxic-Ischemic All trials of Wharton's jelly-derived mesenchymal stem cells All trials of 0.9 % Normal Saline
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.
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.
| Arm | Type | Interventions | Description |
|---|---|---|---|
| Wharton's jelly-derived mesenchymal stem cells | Experimental | Biological: 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. |
| Placebo | Placebo comparator | Drug: 0.9 % Normal Saline | 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. |
Sex: All, ages: 4 Days to 9 Days
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
| Facility | City | Country | Status |
|---|---|---|---|
| Siriraj Hospital, Mahidol University | Bangkok | Thailand |