Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2a Study

Abstract

Background and purpose: Preclinical data suggest that cell-based therapies have the potential to improve stroke outcomes.

Methods: Eighteen patients with stable, chronic stroke were enrolled in a 2-year, open-label, single-arm study to evaluate the safety and clinical outcomes of surgical transplantation of modified bone marrow-derived mesenchymal stem cells (SB623).

Results: All patients in the safety population (N=18) experienced at least 1 treatment-emergent adverse event. Six patients experienced 6 serious treatment-emergent adverse events; 2 were probably or definitely related to surgical procedure; none were related to cell treatment. All serious treatment-emergent adverse events resolved without sequelae. There were no dose-limiting toxicities or deaths. Sixteen patients completed 12 months of follow-up at the time of this analysis. Significant improvement from baseline (mean) was reported for: (1) European Stroke Scale: mean increase 6.88 (95% confidence interval, 3.5-10.3; P<0.001), (2) National Institutes of Health Stroke Scale: mean decrease 2.00 (95% confidence interval, -2.7 to -1.3; P<0.001), (3) Fugl-Meyer total score: mean increase 19.20 (95% confidence interval, 11.4-27.0; P<0.001), and (4) Fugl-Meyer motor function total score: mean increase 11.40 (95% confidence interval, 4.6-18.2; P<0.001). No changes were observed in modified Rankin Scale. The area of magnetic resonance T2 fluid-attenuated inversion recovery signal change in the ipsilateral cortex 1 week after implantation significantly correlated with clinical improvement at 12 months (P<0.001 for European Stroke Scale).

Conclusions: In this interim report, SB623 cells were safe and associated with improvement in clinical outcome end points at 12 months.

Clinical trial registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01287936.

Keywords: Notch 1; allogeneic transplantation; mesenchymal stromal cells; phase 1 clinical trial; stem cells; stereotactic techniques; stroke.

Figure 1

A–D, Change of clinical outcome end points from baseline for pooled SB623 cells at 12 months (intent-to-treat population, n=18). (A) European Stroke Scale. (B) National Institutes of Health Stroke Scale. (C) Fugl-Meyer (F-M) total score. (D) F-M motor function total score. Error bars represent SEM. P values represent significance of change vs baseline using the Wilcoxon signed-rank test (P<0.05), which were not corrected for multiplicity.

Figure 2

A–D, MR brain scans from a 39-year-old female patient, transplanted with SB623 cells 2 years after a left middle cerebral artery stroke. (A left) Axial T2 FSE pretransplant showing the subcortical and cortical infarct. (A right) Pretransplant at higher axial level. (B) Day 1 post-transplant at higher axial level demonstrating small amount of blood in left frontal sulci. (C) Day 7 post-transplant at higher axial level showing new T2 FLAIR signal abnormality in left superior frontal gyrus adjacent to premotor gyrus. (D) Month 2 post-transplant at higher axial level showing resolution of T2 FLAIR signal abnormality. FLAIR indicates fluid-attenuated inversion recovery; FSE, fast spin echo; and MR, magnetic resonance.