Mesenchymal Stromal Cell Implants for Chronic Motor Deficits After Traumatic Brain Injury: Post Hoc Analysis of a
David O Okonkwo1, Peter McAllister1, Achal S Achrol1
1From the Department of Neurological Surgery (D.O.O.), University of Pittsburgh Medical Center, PA; New England Institute for Neurology and Headache (P.M.), Stamford, CT; Department of Neurosurgery (A.S.A.), Loma Linda University Medical Center, CA; Department of Neurosurgery (Y.K.), The University of Tokyo Hospital, Japan; Department of Neurosurgery (M.K.), Hokkaido University Hospital, Sapporo, Japan; Department of Neurology (S.C.C.), University of California, Los Angeles; Westview Clinical Research (A.L.), Placentia, CA; Department of Translational Neurosciences (S.K.), Providence Saint John's Health Center, Santa Monica, CA; The Neurology Center of Southern California (B.M.F.), Carlsbad, CA; Department of Neurology (L.I.G.), University of California, Irvine; UCSF Weill Institute for Neurosciences (A.S.K.), Department of Neurology, University of California, San Francisco; Department of Neurology and Neurological Sciences (N.E.S.), and Stanford Stroke Center, Stanford University School of Medicine and Stanford Health Care, CA; Department of Neurological Surgery (J.W.C.), University of California, Irvine; JCHO Tokyo Shinjuku Medical Center (H.I.), Japan; Department of Neurological Surgery (T.Y.), Okayama University Graduate School of Medicine, Japan; SanBio, Inc. (D.C., B.N., D.B.), Mountain View, CA; Watson & Stonehouse Enterprises LLC (A.H.S.), Pacific Grove, CA; Massachusetts General Hospital and Harvard Medical School (R.M.R.), Boston; Department of Neurosurgery and Stanford Stroke Center (G.K.S.), Stanford University School of Medicine and Stanford Health Care, CA; Biostatistical Consulting Inc. (E.C.P.), Mountain View, CA; and Neurotrauma Rehabilitation Associates LLC (A.H.W.), Littleton, CO.
Background And Objectives:
Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI.
Methods:
Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks.
Results:
A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events.
Discussion:
Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI.
Trial Registration Information:
ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492.
Classification Of Evidence:
This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.
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