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Neurology
Neurology
neurology
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NEUROLOGY
Neurology
0028-3878
1526-632X
Lippincott Williams & Wilkins Hagerstown, MD

WNL-2023-005494
10.1212/WNL.0000000000209797
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20
242
264
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Research Article
Mesenchymal Stromal Cell Implants for Chronic Motor Deficits After Traumatic Brain Injury
Post Hoc Analysis of a Randomized Trial
https://orcid.org/0000-0002-7444-2851
Okonkwo David O. MD, PhD
McAllister Peter MD
Achrol Achal S. MD
Karasawa Yasuaki MD, PhD
https://orcid.org/0000-0002-3574-8380
Kawabori Masahito MD, PhD
https://orcid.org/0000-0002-6214-6211
Cramer Steven C. MD
Lai Albert MD
Kesari Santosh MD, PhD
Frishberg Benjamin M. MD
Groysman Leonid I. MD
https://orcid.org/0000-0002-8095-6517
Kim Anthony S. MD, MAS
Schwartz Neil E. MD, PhD
Chen Jefferson W. MD, PhD
Imai Hideaki MD, PhD
Yasuhara Takao MD, PhD
Chida Dai PhD
Nejadnik Bijan MD
Bates Damien MD, PhD
Stonehouse Anthony H. PhD
https://orcid.org/0000-0003-2620-7387
Richardson R. Mark MD, PhD
Steinberg Gary K. MD, PhD
Poggio Eugene C. PhD
Weintraub Alan H. MD
From 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.
Correspondence Dr. Okonkwo okonkwodo@upmc.edu
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

The Article Processing Charge was funded by SanBio.

Submitted and externally peer reviewed. The handling editor was Associate Editor Rebecca Burch, MD.

8 10 2024
4 9 2024
4 9 2024
103 7 e20979731 8 2023
10 7 2024
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.
2024
American Academy of Neurology
https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

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.

OPEN-ACCESSTRUE
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pmcIntroduction

Traumatic brain injury (TBI) is recognized among worldwide trauma-related injuries as the greatest contributor to death and disability.1 In 2018, the global incidence of all-cause, all-severity TBI was estimated to be 69 million cases per year while in 2016, the global prevalence of chronic impairment secondary to TBI was estimated to be 55.5 million cases.2,3 Advances in acute clinical care have improved post-TBI survival rates, yet there are no approved therapies for TBI, and many participants experience lifelong disabilities as shown by static return-to-work rates over the past 50 years.4-8

The prevalence of TBI-related long-term disabilities varies around the world, ranging from 1,766 per 100,000 persons in the United States to 704 per 100,000 persons in France.9,10 In the United States, long-term motor deficits are reported to be experienced by approximately 43% of participants who were hospitalized with TBI while approximately 5.3 million people live with a TBI-related disability.11,12 In addition, more than one-third of participants with severe TBI are reported to have at least 1 neuromotor impairment 2 years after acute rehabilitation.13 Despite improvements in the treatment of acute TBI, long-term motor deficits secondary to TBI remain a major unmet medical need.

The potential of cell therapies to be safe and effective treatments for the recovery of impairments that are associated with chronic TBI has been demonstrated in several early-stage clinical studies.14-17 Allogeneic modified bone marrow–derived mesenchymal stromal (SB623) cells are in clinical development for chronic motor deficits (e.g., hemiparesis beyond 1 year after injury) secondary to TBI and stable ischemic stroke (SanBio, Inc., Mountain View, CA). In a 2-year phase 1/2a study (NCT01287936), intracerebral implantation of SB623 cells in participants with chronic ischemic stroke was safe and associated with sustained significant improvement of measures of motor status.18

In the primary analysis at 24 weeks of the 1-year, double-blind, randomized, surgical sham-controlled, phase 2 “Stem Cell Therapy for Traumatic Brain Injury” (STEMTRA) trial (NCT02416492), which investigated the intracerebral implantation of SB623 cells in participants with chronic motor deficits after TBI, the authors reported comparable rates of adverse events in both the SB623 pooled and control arms, and that the primary efficacy end point of significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score was achieved for the SB623 pooled vs control arms at 24 weeks.17 However, secondary end points of improvement of function and activities of daily living (ADL) did not significantly change from baseline for the SB623 pooled vs control arms at 24 weeks.17

In this report, we present a post hoc analysis from the completed STEMTRA trial (additional data at ClinicalTrials.gov: NCT02416492), in which we aimed to assess whether implantation of SB623 cells in participants was safe and could improve chronic motor deficits after TBI at 48 weeks.

The primary research objective of the STEMTRA trial was to evaluate the clinical efficacy of intracerebral implantation of SB623 cells on chronic motor deficits secondary to TBI at 24 weeks after implantation. The secondary research objectives of the STEMTRA trial were to evaluate (1) the effect of intracerebral implantation of SB623 cells on disability parameters and (2) the safety and tolerability of intracerebral implantation of SB623 cells.

Methods

In this report, we present a post hoc analysis of the final 1-year data from the completed STEMTRA trial. Participant baseline characteristics, inclusion and exclusion criteria, data analysis methods, and design of the STEMTRA trial have been described previously in the primary analysis,17 which reported the primary efficacy and secondary end points at 24 weeks. In addition, inclusion and exclusion criteria are delineated in detail in Table 1. CONSORT reporting guidelines were used in the reporting of this study.19

Table 1 Study Inclusion and Exclusion Criteriaa

Inclusion criteria
 • Age 18–75 y
 • Documented history of TBI, with correlated MRI or CT
 • At least 12 mo after TBI
 • Focal cerebral injury able to be identified on MRI (±concomitant diffuse axonal injury)
 • Neurologic motor deficit substantially due to focal cerebral injury observed on MRI
 • GOS-E scores of 3–6 (i.e., moderate or severe disability)
 • Require Motricity Index upper extremity score of 10–81 (at least 2 scores less than 33 with 1 of these less than 25 and at least 1 score greater than 0) and/or a lower extremity score of 10–78 (at least 2 scores less than 33 with 1 of these less than 25 and at least 1 score greater than 0)
 • Able and willing to undergo CT and MRI
 • Must have agreed to the use of antiplatelet, anticoagulant, or nonsteroidal anti-inflammatory drugs in accordance with the anticoagulant guidelines29
 • Participants must be willing to participate in study-related exercises to the extent possible
 • Must have been willing to discontinue herbal or nontraditional medicines 1 wk before and 1 wk after the surgical procedure
 • Ability to undergo all planned neurologic assessments
 • Ability of the participant or legal authorized representative to understand and sign an informed consent	• Uncontrolled systemic illness, including but not limited to hypertension (systolic >150 mm Hg or diastolic >95 mm Hg); diabetes; and renal, hepatic, or cardiac failure
 • Uncontrolled major psychiatric illness, including depression symptoms (CESD-R Scale score of ≥16)
 • Total bilirubin >1.9 mg/dL
 • Serum creatinine >1.5 mg/dL
 • Hemoglobin <10.0 g/dL
 • Absolute neutrophil count <2,000/mm3
 • Absolute lymphocytes <800/mm3
 • Platelet count <100,000/mm3
 • Liver disease documented by AST (SGOT) or ALT (SGPT) ≥2.5× institutional upper limit of normal
 • Serum calcium >11.5 mg/dL
 • Unexplained abnormal preoperative test values (blood tests, ECG, chest X-ray); x-ray evidence of infection; uncontrolled atrial fibrillation or uncontrolled congestive heart failure
 • Presence of craniectomy (without bone flap replacement) or other contraindications to stereotactic surgery
 • Participation in any other investigational trial within 4 wk of initial screening or within 7 wk of study entry
 • Botulinum toxin injection, phenol injection, intrathecal baclofen, or any other interventional treatments of spasticity (except bracing and splinting) within 16 wk of the baseline visit (interventional treatment refers to treatment given with special equipment, which is typically performed in a surgical or procedural type facility—this does not apply to oral medications such as oral baclofen)
 • Ongoing use of herbal or other nontraditional drugs
 • Substance use disorder (per DSM-V criteria, including drug or alcohol)
 • Contraindications to head CT or MRI
 • Pregnant or lactating
 • Women of childbearing potential unwilling to use an adequate birth control method during the 12 mo of the study
 • Any other condition or situation that the investigator believed may interfere with the safety of the participant or the intent and conduct of the study
 • Participants with allergic reactions to the ingredients of SB623, the drugs used when administering SB623, or the drugs used in testing (applicable for Japan only)	
Exclusion criteria
 • History or presence of any other major neurologic diseases
 • Any seizures in the previous 3 mo
 • The presence of contracture at any joints that would have interfered with interpretation of any of the neurologic assessments (e.g., contracture preventing the detection of any increase in the range of motion or ability to perform a task)
 • Other neurologic, neuromuscular, or orthopaedic diseases that limited motor function
 • Clinically significant finding on MRI of the brain not related to TBI
 • Known presence of any malignancy except squamous or basal cell carcinoma of the skin
 • History of CNS malignancy
 • Positive findings on tests for occult malignancy, unless a nonmalignant etiology is confirmed	
a This table was originally presented as Table 1 in the study by Kawabori M, Weintraub AH, Imai H, et al. Cell therapy for chronic TBI: interim analysis of the randomized controlled STEMTRA trial. Neurology. 2021;96(8):e1202-e1214. doi:10.1212/WNL.0000000000011450.

Study Population, Standard Protocol Approvals, Registrations, and Participant Consents

The STEMTRA trial (ClinicalTrials.gov: NCT02416492) enrolled participants with moderate or severe TBI with a Motricity Index upper extremity score of 10–81 (at least 2 scores less than 33 with 1 of these less than 25 and at least 1 score greater than 0) and/or a lower extremity score of 10–78 (at least 2 scores less than 33 with 1 of these less than 25 and at least 1 score greater than 0); with Glasgow Outcome Scale-Extended (GOS-E) scores of 3–6; aged 18–75 years; who were at least 12 months postinjury; and who had chronic motor deficits (e.g., hemiparesis beyond 1 year after injury) that correlated with MRI-observed focal cerebral injury. Participants were instructed on a set of standardized physical therapy exercises (cylinder grasp, thumb raise, stand and squat, walk), which were performed at home each morning and afternoon during the screening period and for the first 6 months of the study. The trial was conducted between June 2016 and March 2019 at a total of 27 sites (21 sites in the United States, 5 sites in Japan, and 1 site in Ukraine). Individual institutional review boards reviewed and approved clinical protocols, and participants or legal authorized representatives provided written informed consent.

SB623 Cells

SB623 cells are allogeneic modified bone marrow–derived mesenchymal stromal cells, which are produced by transient transfection with a plasmid containing the intracellular domain of human Notch-1.20 SB623 cells are produced in a Good Gene, Cellular, and Tissue-based Product Manufacturing Practice facility (Lonza Biologics, Portsmouth, NH). Details of the preparation of SB623 cells have been described previously.18

Randomization and Design

A total of 211 survivors were screened by clinical sites for the STEMTRA trial, of whom 63 participants with stable chronic motor deficits secondary to TBI were randomized using a block size of 4 with an interactive web response system on the day of the surgery. For participants enrolled outside Japan, randomization was stratified by the GOS-E score (i.e., scores 3, 4, 5, or 6); for participants in Japan, randomization was not stratified. The surgeons, cell preparation staff, and operating room staff only became aware of treatment group allocation after randomization. Communication between surgeons and efficacy raters was strictly prohibited. Efficacy raters and study participants were blinded to treatment. Participants were randomized in a parallel 1:1:1:1 ratio to the intent-to-treat population, with 3 SB623-treated groups each having 16 participants receiving single doses of 2.5 × 106, 5.0 × 106, or 10 × 106 cells and a sham surgery control arm with 15 participants (Figure 1). Surgeons were unable to determine safe stereotactic implantation trajectories in 2 participants (1 in the SB623 2.5 × 106 and 1 in the SB623 5.0 × 106 cell dose group); therefore, these participants discontinued from the trial before surgery. As a result, 61 participants enrolled in the STEMTRA trial formed both the modified intent-to-treat (mITT) and safety populations (baseline demographics, Table 2). In this final post hoc analysis, all 61 participants in the mITT and safety populations had completed 48-week evaluations.

Figure 1 CONSORT Flow Diagram

63 participants were randomized to SB623 cell treatment or sham surgery. However, safe stereotactic implantation trajectories could not be determined for 1 participant in the SB623 2.5 × 106 cell dose group and 1 participant in the SB623 5.0 × 106 cell dose group, resulting in both participants discontinuing from the trial before surgery. Both the modified intent-to-treat (mITT) and safety populations (n = 61) contained participants who were randomized and underwent SB623 cell treatment or sham surgery. All 61 participants completed 48-week evaluations.

Table 2 Baseline Demographics of Modified Intent-to-Treat and Safety Populationsa

Characteristic	SB623 cell dose/implantation	Control (n = 15)	Total (N = 61)	
2.5 × 106 (n = 15)	5 × 106 (n = 15)	10 × 106 (n = 16)	Pooled (n = 46)	
Age (y)							
 Mean (SD)	36.7 (13.6)	31.2 (9.2)	34.2 (11.5)	34.0 (11.5)	35.5 (13.0)	34.4 (11.8)	
 Median	34.0	30.3	30.2	32.6	35.4	33.4	
 Range (min–max)	19.8–65.2	18.5–53.1	18.9–53.0	18.5–65.2	18.8–67.5	18.5–67.5	
Sex, n (%)							
 Male	11 (73.3)	12 (80.0)	11 (68.8)	34 (73.9)	9 (60.0)	43 (70.5)	
 Female	4 (26.7)	3 (20.0)	5 (31.3)	12 (26.1)	6 (40.0)	18 (29.5)	
Time since injury (mo)							
 Mean (SD)	103.9 (68.0)	82.0 (67.9)	94.3 (76.4)	93.6 (10.6)	99.3 (23.1)	95.0 (9.7)	
 Median	86.5	42.6	69.7	72.9	62.4	68.9	
 Range (min–max)	20.2–242.2	19.0–240.1	16.8–341.2	16.8–341.2	28.0–336.7	16.8–341.2	
Race, n (%)							
 White	11 (73.3)	9 (60.0)	11 (68.8)	31 (67.4)	11 (73.3)	42 (68.9)	
 Black	0 (0.0)	1 (6.7)	0 (0.0)	1 (2.2)	0 (0.0)	1 (1.6)	
 Asian	4 (26.7)	5 (33.3)	5 (31.3)	14 (30.4)	4 (26.7)	18 (29.5)	
Ethnicity, n (%)							
 Hispanic or Latino	0 (0.0)	1 (6.7)	1 (6.3)	2 (4.3)	0 (0.0)	2 (3.3)	
 Not Hispanic or Latino	15 (100)	14 (93.3)	15 (93.8)	44 (95.7)	15 (100)	59 (96.7)	
a This table is based on data that were originally presented in Table 2 of the study by Kawabori M, Weintraub AH, Imai H, et al. Cell therapy for chronic TBI: interim analysis of the randomized controlled STEMTRA trial. Neurology. 2021;96(8):e1202-e1214. doi:10.1212/WNL.0000000000011450.

Sample Size Calculation

A sample size of 48 participants (36 in the SB623 treatment arm and 12 in the control arm) was determined as an appropriate sample size. This required a 2-sample t test to show superiority of the SB623 pooled arm over sham control, assuming 80% power, alpha of 0.05, a 2-tailed test, and 3:1 randomization. This assumed that the mean change from baseline at 24 weeks in the FMMS score was 10 points for the SB623 treatment arm and 3 points for the control arm, with an assumed SD of 7.25 per arm. Based on an 8% upward adjustment to compensate for dropout participants, a total of approximately 52 participants were required. The primary analysis was conducted at 24 weeks and the final post hoc analysis at 48 weeks after implantation follow-up.

Stereotactic Surgical Procedure

SB623 cells were implanted into participants using a stereotactic surgical procedure by burr-hole craniostomy to the peritrauma brain tissue area responsible for the motor deficits as identified by MRI and described previously.18 Sham surgery control participants received a similar stereotactic burr-hole surgical procedure without penetration of the inner table or dura mater, followed by surgical closure of the scalp to maintain blinding of the participant and clinical efficacy and safety assessors.

Study Visit Schedule

STEMTRA trial participants attended the following visit schedule: screen (study day −84 to −15); baseline (study day −14 to −1); cell implantation or sham surgical procedure (day 1); visits (days 2, 8; months 1, 3, 6, 9); final visit (month 12). Clinical TBI evaluations were performed at baseline and months 1, 3, 6, 9, and 12.

Trial Blinding

Efficacy assessments were performed by site-specific neurologists, physiatrists, and physical therapists who were trained in the assessments, and training certification was confirmed and documented by the clinical research organization, with recertification occurring every 6 months; all health care professionals evaluating efficacy were blind to participant treatment. Treatment-emergent adverse events were evaluated by rehabilitation physicians who were also blind to participant treatment. Unblinding events occurred to 2 study participants and their caregivers; however, in both cases, health care professionals who evaluated efficacy remained blind to the participant treatment group.

Efficacy End Points

The focus of SB623 cells is to treat participants with chronic TBI who have persistent deficits in the motor domain of neurologic function; as such, the STEMTRA trial end points addressed the 3 primary levels of human functioning consistent with the World Health Organization's International Classification of Functioning, Disability and Health: (1) impairment (body function and structure); (2) disability (activity); and (3) handicap (participation).21

Impairment was assessed using the FMMS, a broadly accepted measure of motor impairment, as the primary efficacy end point at 24 weeks.22-24 Disability was assessed using the Action Research Arm Test (ARAT) and gait velocity (GV), measures of upper and lower extremity motor functions, respectively.25-27 Handicap was assessed using NeuroQOL upper and lower extremity function T scores (NeuroQOL upper and lower scores), measures of ADL and mobility, respectively.28 Global outcome was assessed using the Disability Rating Scale (DRS) to track general functional change over time.29 The secondary end points were DRS, ARAT, GV, and NeuroQOL upper and lower scores and Global Rating of Perceived Change, each at 24 weeks.17 In this post hoc analysis, FMMS, DRS, ARAT, GV, and NeuroQOL upper and lower scores were assessed at 48 weeks.

Safety

Treatment-emergent adverse events (TEAEs) were assessed and reported by study investigators and were defined as any event that was not present before the initiation of cell treatment or surgical procedure, or any event that was already present which worsened in either intensity or frequency after exposure to cell treatment or surgical procedure. TEAEs were graded as follows: (1) mild, (2) moderate, (3) severe, or (4) life-threatening. The relationship between TEAEs and cell treatment or surgical procedure was determined by the investigator's clinical judgment, using guidance from eTable 1. Participants were instructed to report TEAEs spontaneously or in response to nondirected questioning, with TEAE reporting starting when survivors were assessed for eligibility and finishing 12 months after SB623 cell treatment.

Statistics

Categorical variables were summarized by frequencies and percentages in each category. Descriptive statistics were calculated for continuous variables, including participant number, mean, SD, median, minimum, and maximum.

For efficacy end points in this post hoc analysis, a mixed model of repeated measures (MMRM) using an unstructured covariance matrix for the restricted maximum likelihood estimation procedure was used to compare the SB623 pooled with control arms and SB623 5 × 106 cell dose with control arms. The MMRM model included the following terms: treatment, visit, treatment-by-visit interaction, baseline score, baseline score–by-visit interaction, GOS-E score at screening, and GOS-E score at screening–by-visit interaction. In addition, for efficacy end points, a post hoc responder analysis of SB623 pooled participants was conducted for participants who achieved a change of the FMMS score from baseline of ≥8 at 24 and 48 weeks (responder vs nonresponder).

For safety comparisons, the Fisher exact test was used to analyze the percentage of participants experiencing at least 1 TEAE.

p = 0.05 was considered as statistically significant. Data analyses were performed using SAS version 9.4 (Cary, NC).

Data Availability

Individual deidentified participant data, study protocol, statistical analysis plan, clinical study report, and informed consent forms will be available to qualified external medical and scientific researchers. Data sharing requests may be submitted on publication of this article, with no end date for eligibility. Qualified medical and scientific researchers may submit a data sharing request containing research objectives, data requirements, statistical analysis plan, end points/outcomes of interest, scientific value and impact, and a publication plan to the Chief Medical Officer of SanBio, Inc. The scientific appropriateness of the request will be reviewed by SanBio, Inc.

The study protocol and statistical analysis plan for the STEMTRA trial are available in eSAP 1.

Results

Efficacy Outcomes

The primary efficacy end point of significantly greater change of the FMMS score from baseline at 24 weeks for the SB623 pooled vs control arm 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),17 with SB623-treated participants experiencing higher scores and faster paced improvement of the FMMS score compared with controls at 24 weeks and sustained improvement at 48 weeks after treatment (Figure 2A).

Figure 2 SB623 Efficacy End Point Measures

(A) FMMS mean change from baseline for (1) the SB623 pooled arm at 24 weeks (●), (2) SB623 5 × 106 cell dose at 24 weeks (▲), and (3) SB623 5 × 106 cell dose at 48 weeks (▼). FMMS baseline mean (SD) scores were 52.2 (19.3) for SB623 pooled, 51.3 (22.0) for the 5 × 106 cell dose, and 52.3 (15.1) for sham surgery control. The graphs show data from the modified intent-to-treat population, which included 61 participants who underwent surgery. (B) DRS baseline mean (SD) scores were 4.8 (3.0) for SB623 pooled and 3.7 (2.0) for sham surgery control. The graph shows data from the modified intent-to-treat population, which included 61 participants who underwent surgery. (C) ARAT baseline mean (SD) scores were 19.1 (19.5) for SB623 pooled and 20.1 (17.2) for sham surgery control. The graph shows data from the modified intent-to-treat population, which included 61 participants who underwent surgery. (D) NeuroQOL upper baseline mean (SD) scores were 32.5 (12.9) for SB623 pooled and 32.2 (9.2) for sham surgery control. The graph shows data from the modified intent-to-treat population, which included 61 participants who underwent surgery. (E) Gate velocity baseline mean (SD) scores were 0.67 (0.49) m/s for SB623 pooled and 0.81 (0.58) m/s for sham surgery control. The graph shows data from the lower extremity deficit population (N = 56). (F) NeuroQOL lower baseline mean (SD) scores were 41.5 (10.4) for SB623 pooled and 44.3 (9.6) for sham surgery control. The graph shows data from the modified intent-to-treat population, which included 61 participants who underwent surgery. ARAT = Action Research Arm Test; DRS = Disability Rating Scale; FMMS = Fugl-Meyer Motor Scale.

Participants treated with the SB623 5 × 106 cell dose (n = 15) had significantly greater change of the FMMS score from baseline vs control at 24 weeks (SB623 5 × 106 cell dose: +10.9 [1.8]; 95% CI 7.3–14.6 vs control: +2.4 [1.8]; 95% CI −1.2 to 6.0; p = 0.002) and 48 weeks (SB623 5 × 106 cell dose: +10.5 [1.8]; 95% CI 6.7–14.3 vs control: +4.1 [1.8]; 95% CI 0.3–7.9; p = 0.02) (Figure 2A).

Although pooled SB623-treated participants experienced improvement of the FMMS score from baseline at 48 weeks, this was not significantly different from control (SB623: +7.5 [1.3]; 95% CI 4.9–10.1 vs control: +4.1 [2.2]; 95% CI −0.3 to 8.6; p = 0.20). Notably, change of the FMMS score from baseline was significant for the SB623-treated participants but not control participants at 24 and 48 weeks.

At 48 weeks, the DRS score was not significantly improved from baseline in both the SB623 pooled and control arms, although the point estimate of improvement in the SB623 pooled arm was greater than in the control arm (SB623: −0.3 [0.2]; 95% CI −0.8 to 0.1 vs control: −0.1 [0.4]; 95% CI −0.9 to 0.7; p = 0.61) (Figure 2B). At 48 weeks, ARAT (SB623: +3.1 [1.2]; 95% CI 0.6–5.7 vs control: +1.8 [2.1]; 95% CI −2.5 to 6.1; p = 0.59) (Figure 2C), NeuroQOL upper (SB623: +3.6 [1.2]; 95% CI 1.2–6.1 vs control: +1.2 [2.1]; 95% CI −3.1 to 5.4; p = 0.32) (Figure 2D), GV (SB623: +0.26 [0.06]; 95% CI 0.13–0.38 vs control: +0.05 [0.11]; 95% CI −0.17 to 0.27; p = 0.32) (Figure 2E), and NeuroQOL lower (SB623: +4.6 [0.9]; 95% CI 2.8–6.5 vs control: +1.0 [1.7]; 95% CI −2.3 to 4.4, p = 0.07) (Figure 2F) scores were significantly improved from baseline in the SB623 pooled arm, and the point estimates were greater than in the control arm; however, differences between the SB623 pooled and control arms were not statistically significant.

In a post hoc responder analysis of SB623 pooled participants defined by a FMMS change from baseline of ≥8 points at 24 weeks (defined as the FMMS minimally clinically important difference in chronic TBI),30 improvement of DRS, ARAT, GV, and NeuroQOL upper and lower scores was consistently greater in the responder group than in the nonresponder group at 24 and 48 weeks (Table 3).

Table 3 SB623 Efficacy End Points at 24 and 48 Weeks by FMMS Responder Status (SB623 Pool Responder: FMMS Change From Baseline ≥8 Points at 24 Weeks)

Mean (SD)	SB623 pooled responder	SB623 pooled nonresponder	
Baseline	CFB 24 Weeks	CFB 48 Weeks	Baseline	CFB 24 Weeks	CFB 48 Weeks	
FMMS	50.0 (16.4)	18.0 (8.1)	15.6 (6.2)	54.0 (21.4)	1.0 (4.7)	1.3 (6.0)	
n = 20	n = 20	n = 19	n = 26	n = 26	n = 26	
DRS	5.2 (4.1)	−0.9 (2.8)	−0.9 (2.8)	4.6 (2.0)	−0.5 (1.4)	−0.3 (1.5)	
n = 19	n = 19	n = 18	n = 26	n = 26	n = 26	
ARAT	25.0 (21.8)	5.6 (8.6)	6.1 (8.9)	21.8 (22.3)	−0.7 (5.0)	0.4 (3.8)	
n = 20	n = 20	n = 19	n = 26	n = 26	n = 26	
GV (m/s)	0.691 (0.532)	0.263 (0.330)	0.400 (0.572)	0.621 (0.453)	0.026 (0.282)	0.116 (0.300)	
n = 20	n = 20	n = 18	n = 25	n = 25	n = 25	
NeuroQOL upper	29.55 (13.45)	4.83 (9.43)	5.53 (8.46)	37.14 (11.80)	1.57 (6.21)	2.35 (8.96)	
n = 20	n = 20	n = 19	n = 26	n = 26	n = 26	
NeuroQOL lower	39.65 (10.38)	4.33 (5.41)	5.85 (6.07)	41.79 (10.34)	1.39 (7.29)	3.54 (6.54)	
n = 20	n = 20	n = 19	n = 26	n = 26	n = 26	
Abbreviations: ARAT = Action Research Arm Test; CFB = change from baseline; DRS = Disability Rating Scale; FMMS = Fugl-Meyer Motor Scale; GV = gait velocity.

In addition, there were no clear relationships between FMMS change from baseline at 24 and 48 weeks and time since injury for both the SB623 pooled (mean [SD] 93.6 [10.6] months) and control arms (99.3 [23.1] months).

Safety Outcomes

At 48 weeks, each SB623-treated and control participant experienced at least 1 TEAE, with headache being the most commonly reported TEAE (SB623: 23 participants [50%] vs control: 5 participants [33.3%]) (eTable 2). Overall, there was no significant difference in the rate of TEAEs between SB623 pooled and control participants (p = 0.25), and there was no relationship between the frequency of TEAEs and SB623 cell dose. For both SB623-treated and control participants, greater than 90% of TEAEs were not related or unlikely to be related to cell treatment while greater than 30% of TEAEs were possibly, probably, or definitely related to the surgical procedure (Table 4). TEAEs occurring by relationship to cell treatment and surgical procedure can be found in eTables 3 and 4, respectively.

Table 4 Unique Treatment-Emergent Adverse Events Related to Cell Treatment and Surgical Procedure

Treatment group	Not related (%)	Unlikely related (%)	Possibly related (%)	Probably related (%)	Definitely related (%)	Total number of events, n (%)	
Relationship to cell treatment							
 SB623	74.8	19.1	5.3	0.8	0	246 (100)	
 Control	75.3	19.8	4.9	0	0	81 (100)	
Relationship to surgical procedure							
 SB623	54.9	6.9	12.6	13.0	12.6	246 (100)	
 Control	59.3	9.9	14.8	3.7	12.3	81 (100)	

Through 48 weeks, treatment-emergent serious adverse events (TESAEs) were experienced by 4 SB623-treated participants (8.7%) (6 TESAEs) compared with 3 control participants (20%) (3 TESAEs) (Table 5). Most of the TESAEs were not related to cell treatment and were not related or unlikely to be related to the surgical procedure (Table 5). At 48 weeks, all TESAEs had resolved with the exception of worsening of poor balance experienced by Participant 4, which was ongoing.

Table 5 Treatment-Emergent Serious Adverse Events

Cell dose/implantation	Serious adverse event	Relationship to cell treatment	Relationship to surgical procedure	
2.5 × 106	Participant 1: delirium (postoperative days 3–7)	Not related	Not related	
5 × 106	Participant 2: transient ischemic attack (postoperative days 97–106)	Not related	Not related	
10 × 106	Participant 3: seizure (postoperative day 66–67)	Unlikely related	Possibly related	
10 × 106	Participant 3: seizure (postoperative day 360–367)	Not related	Not related	
10 × 106	Participant 4: delirium (postoperative days 1–3)	Possibly related	Probably related	
10 × 106	Participant 4: worsening of poor balance (postoperative day 136 and ongoing)	Unlikely related	Probably related	
Control	Participant 5: wound infection (postoperative days 153–170)	Not related	Definitely related	
Control	Participant 6: bicycle fall (accident) (postoperative days 148–149)	Not related	Not related	
Control	Participant 7: seizure (postoperative day 227)	Unlikely related	Unlikely related	

In the trial, 4 participants had preexisting anti-SB623 HLA antibodies and a single participant without preexisting anti-SB623 HLA antibodies developed posttreatment anti-SB623 antibodies (a possible sensitization response). At 48 weeks, there were no clinically meaningful trends in vital signs or hematologic or biochemical parameters and no apparent relationships between anti-SB623 HLA antibodies and SB623 cell dose, anti-SB623 HLA antibodies and TESAEs, and anti-SB623 HLA antibodies and efficacy end points. Furthermore, there were no deaths or dose-limiting toxicities, and no participants withdrew because of adverse events.

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.

Discussion

In this randomized trial, intraparenchymal implantation of SB623 mesenchymal stromal cells significantly improved motor status at 24 weeks (the primary efficacy end point) in participants with chronic deficits after TBI, with continued improvement of function and ADL scores at 48 weeks in this post hoc analysis, compared with control participants. SB623 cell implantation was safe and well tolerated.

The FMMS is a broadly accepted measure of motor impairment that is widely used to assess chronic stroke clinical trials.18,22-24,31,32 In the STEMTRA trial, the primary efficacy end point of significantly greater change of the FMMS score from baseline at 24 weeks for the SB623-treated pooled vs control arms was achieved, with SB623-treated pooled participants experiencing faster paced improvement at 24 weeks compared with control participants. In a post hoc analysis, SB623-treated pooled participants experienced sustained improvement of FMMS scores at 48 weeks; however, these were not significantly different compared with control participants. The improvement of FMMS scores from baseline for control participants between 24 and 48 weeks may be the residual effect of the standardized physical therapy exercises that were performed by all participants for the first 24 weeks of the study. Notably, FMMS change from baseline was significant for SB623-treated pooled participants but not for control participants at both 24 and 48 weeks.

Participants treated with the SB623 5 × 106 cell dose experienced significantly greater change of FMMS scores from baseline compared with control at 24 and 48 weeks. Moreover, participants treated with the SB623 5 × 106 cell dose experienced faster paced improvement of motor scores than control participants, which peaked at 24 weeks and was sustained to 48 weeks. Consistent with our primary report,17 these findings suggest that the SB623 5 × 106 cell dose also gave the most favorable outcomes at 48 weeks.

Efficacy end points of ARAT, GV, and NeuroQOL upper and lower scores that assessed function and ADL were significantly improved from baseline in the SB623-treated pooled arm but were not significantly different from those in the control arm at 48 weeks. Further improvements in function or ADL may require more aggressive rehabilitation in addition to tissue regeneration, remodeling, or repair by cell therapy to produce greater degrees of functional recovery.33

Improvement of DRS, ARAT, GV, and NeuroQOL upper and lower scores was greater in a post hoc responder subgroup of SB623 pooled participants who achieved a FMMS change from baseline of ≥8 points at 24 weeks, than in the nonresponder group, suggesting that improvement of motor impairment could lead to improvements of function and ADL. It is also noteworthy that the STEMTRA trial was not powered to detect change in DRS, ARAT, GV, and NeuroQOL upper and lower scores, and that ARAT and NeuroQOL upper and lower scores had ceiling and floor effects that reduced sensitivity.

Consistent with 24-week primary data, there was no significant difference in the rate of treatment-emergent adverse events between SB623 pooled and control participants at 48 weeks, with headache being the most commonly reported adverse event.17 Consistent with earlier studies, greater than 90% of TEAEs were not related or unlikely to be related to cell treatment while greater than 30% of TEAEs were possibly, probably, or definitely related to the stereotactic surgical procedure.18,34

Consistent with an earlier phase 1/2a study (NCT01287936) of SB623 cells for the treatment of chronic ischemic stroke,18 there were no apparent relationships between anti-SB623 HLA antibodies and cell dose, serious adverse events, or efficacy end points in the STEMTRA trial, demonstrating the low immunoreactive potential of allogeneic SB623 cells implanted in the brain even in the absence of immunosuppressive agents.

The STEMTRA trial is the world's first double-blind, randomized, surgical sham-controlled cell implantation therapy study for treatment of chronic motor deficits secondary to TBI. As yet, there are insufficient data to define precisely the optimal implantation site of SB623 cells in relation to the site of TBI injury, which may be diffuse in nature. As a result, SB623 cell implantation sites were determined by the surgeon's judgment, which reflected real-world practice but may have caused variability of participant responses. Variability of participant responses may have also been caused by the wide participant age range, incidence of comorbidities, differences in external environmental factors, and variability of postsurgery physical therapy. Moreover, despite the STEMTRA trial being surgically sham-controlled, improvement of outcome measures may have been caused by surgical manipulation of peri-injured tissue instead of the effects of implanted SB623 cells. The authors note that, although this study was conducted across a total of 27 sites in the United States, Japan, and Ukraine, most participants were White (68.9%), with a minority of Asian participants (29.5%) and a single Black participant (1.6%).

We report a post hoc analysis of the completed 1-year, double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492). SB623-treated participants experienced higher scores and faster paced improvement on the primary efficacy end point of the FMMS score compared with control participants at 24 weeks, with sustained improvement at 48 weeks. Improvement of function and ADL scores trended to be greater in SB623-treated participants compared with control participants at 48 weeks. Implantation of SB623 cells was safe. Future clinical development should focus on the 5 × 106 SB623 cell dose because the motor score change from baseline was significantly higher than in control at both 24 weeks and 48 weeks, particularly as improvement of motor status may have relevance to improved quality of life.

Acknowledgment

The authors and investigators thank the participants and their families from the STEMTRA trial for their trust and partnership.

Study Funding

No targeted funding reported.

Disclosure

D.O. Okonkwo, P. McAllister, A.S. Achrol, and Y. Karasawa report no disclosures. M. Kawabori serves as a consultant for SanBio Inc. S.C. Cramer serves as a consultant for Constant Therapeutics, BrainQ, Myomo, MicroTransponder, Panaxium, Elevian, Stream Biomedical, NeuroTrauma Sciences, and TRCare, and previously served as a consultant for SanBio, Inc. A. Lai and S. Kesari report no disclosures. B.M. Frishberg serves as an expert witness for traumatic brain injury. L.I. Groysman reports no disclosures. A.S. Kim received grants from SanBio Inc. to support an Internet participant recruitment registry that was utilized for the submitted work, receives grants from NIH/NCATS, NIH/National Institute of Neurological Disorders and Stroke, PCORI, and AHA that are outside of the submitted work, and receives financial support as an associate editor for NEJM Journal Watch: Neurology that is outside of the submitted work. N.E. Schwartz, J.W. Chen, H. Imai, and T. Yasuhara report no disclosures. D. Chida is an employee of SanBio Inc. B. Nejadnik is a former employee of and currently serves as a consultant for SanBio Inc. D. Bates is a former employee of and previously served as a consultant for SanBio Inc. A.H. Stonehouse serves as a consultant for SanBio Inc. R.M. Richardson previously served as a consultant for SanBio Inc. G.K. Steinberg serves as a consultant for SanBio Inc., Zeiss, and Surgical Theater, and receives royalties from Peter Lazic, US. E.C. Poggio serves as a consultant for SanBio Inc. A.H. Weintraub is the owner of Neurotrauma Rehabilitation Associates LLC, Littleton, CO; serves as a contracted Medical Director for Paradigm Corporation, previously served as a contract research scientist for the Craig Hospital, Englewood, CO (2020–2022); previously served as an employee and shareholder for the CNS Medical Group, Englewood, CO (1986–2020); previously served as a consultant for SanBio Inc., and receives fees for periodic forensic medical legal consultations. Go to Neurology.org/N for full disclosures.

Appendix Authors

Name	Location	Contribution	
David O. Okonkwo, MD, PhD	Department of Neurological Surgery, University of Pittsburgh Medical Center, PA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Peter McAllister, MD	New England Institute for Neurology and Headache, Stamford, CT	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Achal S. Achrol, MD	Department of Neurosurgery, Loma Linda University Medical Center, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Yasuaki Karasawa, MD, PhD	Department of Neurosurgery, The University of Tokyo Hospital, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Masahito Kawabori, MD, PhD	Department of Neurosurgery, Hokkaido University Hospital, Sapporo, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Steven C. Cramer, MD	Department of Neurology, University of California, Los Angeles, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Albert Lai, MD	Westview Clinical Research, Placentia, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Santosh Kesari, MD, PhD	Department of Translational Neurosciences, Providence Saint John's Health Center, Santa Monica, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Benjamin M. Frishberg, MD	The Neurology Center of Southern California, Carlsbad, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Leonid I. Groysman, MD	Department of Neurology, University of California, Irvine, Orange, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Anthony S. Kim, MD, MAS	UCSF Weill Institute for Neurosciences, Department of Neurology, University of California, San Francisco, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Neil E. Schwartz, MD, PhD	Department of Neurology and Neurological Sciences, and Stanford Stroke Center, Stanford University School of Medicine and Stanford Health Care, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Jefferson W. Chen, MD, PhD	Department of Neurological Surgery, University of California, Irvine, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Hideaki Imai, MD, PhD	JCHO Tokyo Shinjuku Medical Center, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Takao Yasuhara, MD, PhD	Department of Neurological Surgery, Okayama University Graduate School of Medicine, Japan	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Dai Chida, PhD	SanBio, Inc, Mountain View, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Bijan Nejadnik, MD	SanBio, Inc, Mountain View, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Damien Bates, MD, PhD	SanBio, Inc, Mountain View, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; study concept or design; analysis or interpretation of data	
Anthony H. Stonehouse, PhD	Watson & Stonehouse Enterprises LLC, Pacific Grove, CA	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
R. Mark Richardson, MD, PhD	Massachusetts General Hospital and Harvard Medical School, Boston, MA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Gary K. Steinberg, MD, PhD	Department of Neurosurgery and Stanford Stroke Center, Stanford University School of Medicine and Stanford Health Care, CA	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	
Eugene C. Poggio, PhD	Biostatistical Consulting Inc, Lexington, MA	Drafting/revision of the manuscript for content, including medical writing for content; analysis or interpretation of data	
Alan H. Weintraub, MD	Neurotrauma Rehabilitation Associates LLC, Littleton, CO	Drafting/revision of the manuscript for content, including medical writing for content; major role in the acquisition of data; analysis or interpretation of data	

Glossary

ADL activities of daily living

ARAT Action Research Arm Test

DRS Disability Rating Scale

FMMS Fugl-Meyer Motor Scale

GOS-E Glasgow Outcome Scale-Extended

GV gait velocity

mITT modified intent-to-treat

MMRM mixed model of repeated measures

STEMTRA Stem Cell Therapy for Traumatic Brain Injury

TBI traumatic brain injury

TEAE treatment-emergent adverse event

TESAE treatment-emergent serious adverse event
==== Refs
References

1. Rubiano AM, Carney N, Chesnut R, Puyana JC. Global neurotrauma research challenges and opportunities. Nature. 2015;527 (7578 ):S193-S197. doi:10.1038/nature16035 26580327
2. Dewan MC, Rattani A, Gupta S, et al . Estimating the global incidence of traumatic brain injury. J Neurosurg. 2019;130 (4 ):1080-1097. doi:10.3171/2017.10.JNS17352 29701556
3. GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators. Global, regional, and national burden of traumatic brain injury and spinal cord injury, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol. 2019;18 (1 ):56-87. doi:10.1016/S1474-4422(18)30415-0 30497965
4. Zoerle T, Carbonara M, Zanier ER, et al . Rethinking neuroprotection in severe traumatic brain injury: toward bedside neuroprotection. Front Neurol. 2017;8 :354. doi:10.3389/fneur.2017.00354 28790967
5. Bleck TP. Historical aspects of critical care and the nervous system. Crit Care Clin. 2009;25 (1 ):153-164. doi:10.1016/j.ccc.2008.12.004 19268800
6. Carney N, Totten AM, O'Reilly C, et al . Guidelines for the management of severe traumatic brain injury, Fourth Edition. Neurosurgery. 2017;80 (1 ):6-15. doi:10.1227/NEU.0000000000001432 27654000
7. London PS. Some observations on the course of events after severe injury of the head. Hunterian Lecture delivered at the Royal College of Surgeons of England on 12th January 1967. Ann R Coll Surg Engl. 1967;41 (6 ):460-479.4229662
8. Cifu DX, Keyser-Marcus L, Lopez E, et al . Acute predictors of successful return to work 1 year after traumatic brain injury: a multicenter analysis. Arch Phys Med Rehabil. 1997;78 (2 ):125-131. doi:10.1016/s0003-9993(97)90252-5 9041891
9. Langlois JA, Rutland-Brown W, Wald MM. The epidemiology and impact of traumatic brain injury: a brief overview. J Head Trauma Rehabil. 2006;21 (5 ):375-378. doi:10.1097/00001199-200609000-00001 16983222
10. Jourdan C, Azouvi P, Genêt F, Selly N, Josseran L, Schnitzler A. Disability and Health Consequences of traumatic brain injury: national prevalence. Am J Phys Med Rehabil. 2018;97 (5 ):323-331. doi:10.1097/PHM.0000000000000848 29016402
11. Selassie AW, Zaloshnja E, Langlois JA, Miller T, Jones P, Steiner C. Incidence of long-term disability following traumatic brain injury hospitalization, United States, 2003. J Head Trauma Rehabil. 2008;23 (2 ):123-131. doi:10.1097/01.HTR.0000314531.30401.39 18362766
12. Thurman DJ, Alverson C, Dunn KA, Guerrero J, Sniezek JE. Traumatic brain injury in the United States: a public health perspective. J Head Trauma Rehabil. 1999;14 (6 ):602-615. doi:10.1097/00001199-199912000-00009 10671706
13. Walker WC, Pickett TC. Motor impairment after severe traumatic brain injury: a longitudinal multicenter study. J Rehabil Res Dev. 2007;44 (7 ):975-982. doi:10.1682/jrrd.2006.12.0158 18075954
14. Sharma A, Sane H, Kulkarni P, et al . Cell therapy attempted as a novel approach for chronic traumatic brain injury: a pilot study. Springerplus. 2015;4 :26. doi:10.1186/s40064-015-0794-0 25628985
15. Sharma AK, Sane HM, Kulkarni PP, Gokulchandran N, Biju H, Badhe PB. Autologous bone marrow mononuclear cell transplantation in patients with chronic traumatic brain injury- a clinical study. Cell Regen. 2020;9 (1 ):3. doi:10.1186/s13619-020-00043-7 32588151
16. Wang S, Cheng H, Dai G, et al . Umbilical cord mesenchymal stem cell transplantation significantly improves neurological function in patients with sequelae of traumatic brain injury. Brain Res. 2013;1532 :76-84. doi:10.1016/j.brainres.2013.08.001 23942181
17. Kawabori M, Weintraub AH, Imai H, et al . Cell therapy for chronic TBI: interim analysis of the randomized controlled STEMTRA trial. Neurology. 2021;96 (8 ):e1202-e1214. doi:10.1212/WNL.0000000000011450 33397772
18. Steinberg GK, Kondziolka D, Wechsler LR, et al . Two-year safety and clinical outcomes in chronic ischemic stroke patients after implantation of modified bone marrow-derived mesenchymal stem cells (SB623): a phase 1/2a study. J Neurosurg. 2018;131 (5 ):1462-1472. doi:10.3171/2018.5.JNS173147 30497166
19. Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ. 2010;340 :c332. doi:10.1136/bmj.c332 20332509
20. Yasuhara T, Matsukawa N, Hara K, et al . Notch-induced rat and human bone marrow stromal cell grafts reduce ischemic cell loss and ameliorate behavioral deficits in chronic stroke animals. Stem Cells Dev. 2009;18 (10 ):1501-1514. doi:10.1089/scd.2009.0011 19301956
21. How to use the ICF: a practical manual for using the International Classification of Functioning, Disability and Health (ICF). Exposure draft for comment October 2013. Accessed September 22, 2022. who.int/publications/m/item/how-to-use-the-icf---a-practical-manual-for-using-the-international-classification-of-functioning-disability-and-health
22. Fugl-Meyer AR, Jääskö L, Leyman I, Olsson S, Steglind S. The post-stroke hemiplegic patient. 1. a method for evaluation of physical performance. Scand J Rehabil Med. 1975;7 (1 ):13-31. doi:10.2340/1650197771331 1135616
23. See J, Dodakian L, Chou C, et al . A standardized approach to the Fugl-Meyer assessment and its implications for clinical trials. Neurorehabil Neural Repair. 2013;27 (8 ):732-741. doi:10.1177/1545968313491000 23774125
24. Gladstone DJ, Danells CJ, Black SE. The Fugl-Meyer assessment of motor recovery after stroke: a critical review of its measurement properties. Neurorehabil Neural Repair. 2002;16 (3 ):232-240. doi:10.1177/154596802401105171 12234086
25. Lyle RC. A performance test for assessment of upper limb function in physical rehabilitation treatment and research. Int J Rehabil Res. 1981;4 (4 ):483-492. doi:10.1097/00004356-198112000-00001 7333761
26. Yozbatiran N, Der-Yeghiaian L, Cramer SC. A standardized approach to performing the action research arm test. Neurorehabil Neural Repair. 2008;22 (1 ):78-90. doi:10.1177/1545968307305353 17704352
27. Rehabilitation Measures Database: 10 Meter Walk Test, last updated January 22, 2014. Accessed May 10, 2024. sralab.org/rehabilitation-measures/10-meter-walk-test.
28. National Institute of Neurological Disorders and Stroke. User Manual for the Quality of Life in Neurological Disorders (Neuro-QoL) Measures: Version 2.0. 2015. Accessed July 12, 2022. healthmeasures.net/images/neuro_qol/Neuro-QOL_User_Manual_v2_24Mar2015.pdf.
29. Rehabilitation Measures Database: Disability Rating Scale (for TBI), last updated December 13, 2012. Accessed May 10, 2024. sralab.org/rehabilitation-measures/disability-rating-scale-tbi.
30. McCrea MA, Cramer SC, Okonkwo DO, et al . Determining minimally clinically important differences for outcome measures in patients with chronic motor deficits secondary to traumatic brain injury. Expert Rev Neurother. 2021;21 (9 ):1051-1058. doi:10.1080/14737175.2021.1968299 34402352
31. Duncan PW, Propst M, Nelson SG. Reliability of the Fugl-Meyer assessment of sensorimotor recovery following cerebrovascular accident. Phys Ther. 1983;63 (10 ):1606-1610. doi:10.1093/ptj/63.10.1606 6622535
32. Sullivan KJ, Tilson JK, Cen SY, et al . Fugl-Meyer assessment of sensorimotor function after stroke: standardized training procedure for clinical practice and clinical trials. Stroke. 2011;42 (2 ):427-432. doi:10.1161/STROKEAHA.110.592766 21164120
33. Cramer SC. Recovery after stroke. Continuum (Minneap Minn). 2020;26 (2 ):415-434. doi:10.1212/CON.0000000000000838 32224759
34. Kondziolka D, Steinberg GK, Wechsler L, et al . Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg. 2005;103 (1 ):38-45. doi:10.3171/jns.2005.103.1.0038 16121971
