Stem cells for bronchopulmonary dysplasia in preterm infants: A randomized controlled phase II trial

Abstract

We previously demonstrated the safety and feasibility of mesenchymal stem cell (MSC) transplantation for bronchopulmonary dysplasia (BPD) in preterm infants in a phase I clinical trial. We thus investigated the therapeutic efficacy of MSCs for BPD in premature infants. A phase II double-blind, randomized, placebo-controlled clinical trial was conducted on preterm infants at 23 to 28 gestational weeks (GW) receiving mechanical ventilator support with respiratory deterioration between postnatal days 5 and 14. Infants were stratified by 23 to 24 GW and 25 to 28 GW and randomly allocated (1:1) to receive stem cells (1 × 10⁷ cells/kg, n = 33) or placebo (n = 33). Although the inflammatory cytokines in the tracheal aspirate fluid were significantly reduced with MSCs, the primary outcome of death or severe/moderate BPD in the control group (18/33, 55%) was not significantly improved with MSC transplantation (17/33, 52%). In the subgroup analysis, the secondary outcome of severe BPD was significantly improved from 53% (8/15) to 19% (3/16) with MSC transplantation in the 23 to 24 GW group but not in the 25 to 28 GW subgroup. In summary, although MSC transplantation might be safe and feasible, this small study was underpowered to detect its therapeutic efficacy in preterm infants at 23 to 28 GW. Accordingly, we are now conducting an additional larger and controlled phase II clinical trial focusing on infants at 23 to 24 GW (NCT03392467). ClinicalTrials.gov identifier: NCT01828957.

Keywords: bronchopulmonary dysplasia; cell transplantation; mesenchymal stem cells; premature infants.

FIGURE 1

Trial profile. Flow chart of participants and visits during the trial. MSC, mesenchymal stem cell

FIGURE 2

Temporal changes in levels of cytokines and growth factors from tracheal aspirate fluid assessed by enzyme‐linked immunosorbent assay in control group and MSC group. Tracheal aspirate fluid was collected before transplantation and at 7 days after transplantation and IL‐1 α/β, IL‐6, IL‐8, MMP‐9, TNF‐α, VEGF, and HGF were measured. The lines depict mean log‐transformation levels of cytokines and growth factors and error bars depict SEM for each group. At baseline, before stem cells or placebo transplantation, no difference in levels of cytokines and growth factors was observed between two groups. At 7 days after transplantation, MSC group showed significantly decreased levels of inflammatory cytokines of IL‐β, IL‐6, IL‐8, MMP‐9, and TNF‐α, when compared with control group. *Values of P for between‐group comparisons computed with the repeated measures analysis of variance were <.05. HGF, hepatocyte growth factor; IL, interleukin; MMP‐9, matrix metalloproteinase‐9; MSC, mesenchymal stem cell; TNF‐α, tumor necrosis factor‐α; VEGF, vascular endothelial growth factor