Potentiation of cord blood cell therapy with erythropoietin for children with CP: a 2 × 2 factorial randomized placebo-controlled trial

Abstract

Background Concomitant administration of allogeneic umbilical cord blood (UCB) infusion and erythropoietin (EPO) showed therapeutic efficacy in children with cerebral palsy (CP). However, no clinical studies have investigated the effects of UCB and EPO combination therapy using a 2 × 2 four-arm factorial blinded design with four arms. This randomized placebo-controlled trial aimed to identify the synergistic and individual efficacies of UCB cell and EPO for the treatment of CP. Methods Children diagnosed with CP were randomly segregated into four groups: (A) UCB+EPO, (B) UCB+placebo EPO, (C) placebo UCB+EPO, and (D) placebo UCB+placebo EPO. Based on the UCB unit selection criteria of matching for ≥ 4/6 of human leukocyte antigen (HLA)-A, -B, and DRB1 and total nucleated cell (TNC) number of ≥ 3 × 107/kg, allogeneic UCB was intravenously infused and 500 IU/kg human recombinant EPO was administered six times. Functional measurements, brain imaging studies, and electroencephalography were performed from baseline until 12 months post-treatment. Furthermore, adverse events were closely monitored. Results Eighty-eight of 92 children enrolled (3.05 ± 1.22 years) completed the study. Change in gross motor performance measure (GMPM) was greater in group A than in group D at 1 month (△2.30 vs. △0.71, P = 0.025) and 12 months (△6.85 vs. △2.34, P = 0.018) post-treatment. GMPM change ratios were calculated to adjust motor function at the baseline. Group A showed a larger improvement in the GMPM change ratio at 1 month and 12 months post-treatment than group D. At 12 months post-treatment, the GMPM change ratios were in the order of groups A, B, C, and D. These results indicate synergistic effect of UCB and EPO combination better than each single therapy. In diffusion tensor imaging, the change ratio of fractional anisotropy at spinothalamic radiation was higher in group A than group D in subgroup of age ≥ 3 years. Additionally, higher TNC and more HLA-matched UCB units led to better gross motor outcomes in group A. Adverse events remained unchanged upon UCB or EPO administration. Conclusions These results indicate that the efficacy of allogeneic UCB cell could be potentiated by EPO for neurological recovery in children with CP without harmful effects. Trial registration ClinicalTrials.gov, NCT01991145, registered 25 November 2013.

Safety of allogeneic umbilical cord blood infusions for the treatment of neurological conditions: a systematic review of clinical studies

“…Two studies [18,19] found that some AEs were attributable to the use of immunosuppression. By contrast, Min et al [20] found no increase in the overall incidence of AEs due to immunosuppression.…”

“…The number of total AEs and SAEs for each study, where available, is reported in Table 2. In all controlled trials with a comparator group [18,20,22,26], the frequency of both AEs and SAEs was similarly distributed between groups. Moreover, across all studies, no SAEs were deemed to be definitely or probably related to allogeneic UCB.…”

“…All participant data from Vyas et al [27] were included in the results, regardless of condition. Of the 10 included studies, four were randomized controlled trials [18,20,22,26], five were single-group allocation studies [21,24,25,27,28] and one was a case report [19].…”

“…Six studies documented methods for stringent maternal infectious disease screening of donor UCB [20,21,23,24,26,27]. Five of these also made note of sterility testing of cryopreserved samples [20,21,23,24,27].…”

“…Three studies specified that allogeneic UCB was ABO blood groupmatched [20,21,24]. One study indicated that UCB that was not ABO blood group-matched was used, as units are commonly red blood cell-depleted [27].…”