3 - Safety and tolerability of a multilineage-differentiating stress-enduring cell-based product in neonatal hypoxic-ischemic encephalopathy with therapeutic hypothermia (SHIELD trial)

Poster Number: 3
Publication Number: 3.284

Background: Hypoxic ischemic encephalopathy (HIE) is an important upstream event related with high mortality and neurological sequelae such as cerebral palsy. No treatment for HIE has yet been established, except for therapeutic hypothermia, whose effect is insufficient, especially in severe cases. Therefore, developing novel therapies for HIE is urgent.
Multilineage-differentiating stress-enduring (Muse) cells are nontumorigenic pluripotent stem cells that are intrinsic to the body and function as repair stem cells. Our previous nonclinical studies using an HIE model showed that administration of a clinical-grade Muse cell product (CL2020) is safe and effective.

Objective: In this exploratory, investigator-initiated clinical trial (SHIELD trial), we evaluated the safety and tolerability of CL2020 administration in neonates with HIE.

Design/Methods: This single-center, open-label, dose-escalation study enrolled nine patients. Neonates with HIE who received a course of therapeutic hypothermia therapy were included.
Each patient received a single intravenous injection of CL2020 cells between 5 and 14 days of age. The low-dose group (3 patients) received 1.5 × 10^6 cells/dose, and high-dose group (6 patients) received 1.5 × 10^7 cells/dose. The primary outcome was the occurrence of any adverse event within 12 weeks after CL2020 administration. Secondary outcomes were the survival rate and neurodevelopment, including the gross motor function classification system (GMFCS) and developmental quotient from the Kyoto Scale of Psychological Development (KSPD) at 78 weeks. The secondary outcomes were compared with data from a national registry of therapeutic hypothermia.

Results: No significant changes in physiological signs—including heart rate, blood pressure, and oxygen saturation—were observed during or after CL2020 administration. The only adverse event that might be related to cell administration was a mild elevation of γGTP in one neonate (which resolved spontaneously without any treatment).
All patients enrolled in the SHIELD trial survived, compared with 92% in the registry. A GMFCS score ≤2 was observed in 89% of SHIELD trial patients, compared with 77% in the registry. A normal score (≥85) in all three domains of the KSPD was observed in 67% of SHIELD trial patients, compared with 33% in the registry.

Conclusion(s): Administration of CL2020 was demonstrated to be safe and tolerable for neonates with HIE. Our results indicate a trend of efficacy of CL2020 treatment; however, given the small number of patients enrolled in this study, a large scale case-control study is warranted to verify these preliminary findings.