A clinical trial of umbilical cord blood and umbilical cord tissue mesenchymal stromal cells in children with cerebral palsy

BACKGROUND AND OBJECTIVE(S): Early phase studies of umbilical cord blood (CB) and mesenchymal stromal cells (MSC) have demonstrated safety in young children with cerebral palsy (CP) with suggestion of potential functional benefits. However, small sample sizes, heterogeneous patient populations, and variable cell doses have hindered the ability to accurately quantify motor improvement following treatment. The objective of the ACCeNT‐CP study was to describe change in gross motor function in young children with CP after treatment with high‐dose allogeneic unrelated donor CB or allogeneic, third party, human cord tissue‐derived MSC (hCT‐MSC) 12 months post treatment STUDY DESIGN: Phase 2, prospective, randomized clinical trial. STUDY PARTICIPANTS & SETTING: Ninety children (median 3.5 years, range 2‐4y) were randomized. Children with hypertonic CP due to hypoxic ischemic encephalopathy, periventricular leukomalacia, or in utero stroke or bleed were eligible if they were Gross Motor Function Classification System (GMFCS) levels I to IV and had no major comorbidities. Children with known genetic conditions, intractable seizures, or prior cell therapy were ineligible. MATERIALS/METHODS: Randomization, stratified by etiology and severity (GMFCS level), was to either: (1) single dose of 10x107 total nucleated cells (TNC)/kg of allogeneic CB at baseline, (2) three doses of 2x106 cells/kg of hCT‐MSC given at baseline, 3, and 6 months, or (3) Natural History in which 10x107 TNC/kg of allogeneic CB was given at 1 year. All infusions were given intravenously after premedication with diphenhydramine and methylprednisolone without immunosuppression. Change in gross motor function was assessed by the Gross Motor Function Measure‐66 (GMFM‐66) at 6 and 12 months. The primary outcome was change in motor function 1‐year post study enrollment. RESULTS: All 90 children completed baseline and 6‐month evaluations. Due to the COVID pandemic, only 68 participants completed the 12‐month assessments. Infusions were well tolerated, with 8 transient infusion reactions (3 CB, 5 hCT‐MSC). There were a total of 128 other adverse events (33 severe, 95 non‐severe), all unrelated to the cell products. At 6 months, there was no statistical difference in change in GMFM‐66 scores between the Natural History arm (n=31) and either of the treatment groups (CB n=31, hCT‐MSC n=28). At 12 months, the mean GMFM‐66 score of the hCT‐MSC group (n=23) was 1.4 points greater than Natural History (n=25; 95% CI:‐1.1, 4.0; p=0.27) and the mean score in the CB group (n=20) was 3.3 points greater than Natural History (95% CI: 0.59, 5.93; p=0.02) after adjustment for baseline GMFCS level, baseline GMFM‐66 score, and etiology of CP. CONCLUSIONS/SIGNIFICANCE: High dose allogeneic CB infusion is associated with gross motor improvement in young children with CP, consistent with the dose effect seen in a prior study of autologous CB. An increase of 3.3 points on the GMFM‐66 exceeds minimum clinically important differences of large effect sizes, and as such is clinically relevant. Treatment with hCT‐MSC was not associated with motor gains. A phase 3 randomized placebo‐controlled study should be performed to confirm the CB observation.