Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial

Masahito Kawabori, Alan H Weintraub, Hideaki Imai, Laroslav Zinkevych, Peter McAllister, Gary K Steinberg, Benjamin M Frishberg, Takao Yasuhara, Jefferson W Chen, Steven C Cramer, Achal S Achrol, Neil E Schwartz, Jun Suenaga, Daniel C Lu, Ihor Semeniv, Hajime Nakamura, Douglas Kondziolka, Dai Chida, Takehiko Kaneko, Yasuaki Karasawa, Susan Paadre, Bijan Nejadnik, Damien Bates, Anthony H Stonehouse, R Mark Richardson, David O Okonkwo, Masahito Kawabori, Alan H Weintraub, Hideaki Imai, Laroslav Zinkevych, Peter McAllister, Gary K Steinberg, Benjamin M Frishberg, Takao Yasuhara, Jefferson W Chen, Steven C Cramer, Achal S Achrol, Neil E Schwartz, Jun Suenaga, Daniel C Lu, Ihor Semeniv, Hajime Nakamura, Douglas Kondziolka, Dai Chida, Takehiko Kaneko, Yasuaki Karasawa, Susan Paadre, Bijan Nejadnik, Damien Bates, Anthony H Stonehouse, R Mark Richardson, David O Okonkwo

Abstract

Objective: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623).

Methods: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 × 106, 5.0 × 106, 10 × 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15).

Results: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25).

Conclusions: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls.

Classification of evidence: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Consort Diagram
Figure 1. Consort Diagram
Intent-to-treat (ITT) population (n = 63): patients randomized to SB623 cell treatment or sham surgery. Modified ITT (mITT) population (n = 61): patients randomized to SB623 treatment or sham surgery, minus 2 patients, 1 each from the SB623 2.5 × 106 and 5.0 × 106 treatment groups who discontinued before treatment because physicians could not determine safe cell injection trajectories. Safety population (n = 61): patients who enrolled and underwent SB623 treatment or sham surgery.
Figure 2. Primary Efficacy Endpoint Measures
Figure 2. Primary Efficacy Endpoint Measures
(A) Fugl-Meyer Motor Scale (FMMS) score change from baseline for SB623 pooled and sham control groups at time points up to 6 months (modified intent-to-treat [mITT] population, n = 61). *p < 0.05. (B) Percent of patients in each treatment group who achieved potentially clinically meaningful improvement of FMMS score (≥10 points) at 6 months (mITT population, n = 61). *p < 0.05. (C) FMMS dose response: change from baseline for each treatment group at time points up to 6 months (mITT population, n = 61). Difference found between the 5.0 × 106 treatment and sham surgery groups was calculated separately and did not include comparisons between other SB623 treatment groups and the sham surgery group. **p < 0.01.

References

    1. James SL, Theadom A, Ellenbogen RG; 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;18:56–87.
    1. 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;23:123–131.
    1. 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;14:602–615.
    1. Walker WC, Pickett TC. Motor impairment after severe traumatic brain injury: a longitudinal multicenter study. J Rehabil Res Dev 2007;44:975–982.
    1. Seledtsov VI, Rabinovich SS, Parlyuk OV, et al. . Cell transplantation therapy in re-animating severely head-injured patients. Biomed Pharmacother 2005;59:415–420.
    1. Cox CS Jr, Hetz RA, Liao GP, et al. . Treatment of severe adult traumatic brain injury using bone marrow mononuclear cells. Stem Cells 2017;35:1065–1079.
    1. 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.
    1. 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;1:1–11.
    1. Aizman I, Tate CC, McGrogan M, Case CC. Extracellular matrix produced by bone marrow stromal cells and by their derivative, SB623 cells, supports neural cell growth. J Neurosci Res 2009;87:3198–3206.
    1. Wechsler LR, Bates D, Stroemer P, Andrews-Zwilling YS, Aizman I. Cell therapy for chronic stroke in focused updates in cerebrovascular disease. Stroke 2018;49:1066–1074.
    1. 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 Cell Dev 2009;18:1501–1514.
    1. Tajiri N, Kaneko Y, Shinozuka K, et al. . Stem cell recruitment of newly formed host cells via a successful seduction? Filling the gap between neurogenic niche and injured brain site. PLoS One 2013;8:e74857.
    1. 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;7:13–31.
    1. 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;27:732–741.
    1. 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;16:232–240.
    1. Rehabilitation Measures Database. Disability Rating Scale (for TBI). 2012. Available at: . Accessed June 2, 2019.
    1. Lyle RC. A performance test for assessment of upper limb function in physical rehabilitation treatment and research. Int J Rehabil Res 1981;4:483–492.
    1. Yozbatiran N, Der-Yeghiaian L, Cramer SC. A standardized approach to performing the action research arm test. Neurorehabil Neural Repair 2008;22:78–90.
    1. Rehabilitation Measures Database. 10 Meter walk test. 2014. Available at: . Accessed June 2, 2019.
    1. National Institute of Neurological Disorders and Stroke. NINDS user manual for the Quality of Life in Neurological Disorders (Neuro-QoL) measures, version 2.0, March 2015. Available at: . Accessed June 2, 2019.
    1. Kamper SJ, Maher CG, Mackay G. Global rating of change scales: a review of strengths and weaknesses and considerations for design. J Man Manip Ther 2009;17:163–170.
    1. Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res 1990;31:545–548.
    1. Kleim JA, Chan S, Pringle E, et al. . BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex. Nat Neurosci 2006;9:735–737.
    1. Cramer SC, Procaccio V. Correlation between genetic polymorphisms and stroke recovery: analysis of the GAIN Americas and GAIN International studies. Eur J Neurol 2012;19:718–724.
    1. Kondziolka D, Steinberg GK, Wechsler L, Meltzer CC, Elder E, Gebel J. Neurotransplantation for patients with subcortical motor stroke: a phase 2 randomized trial. J Neurosurg 2005;103:38–45.
    1. Duncan PW, Propst M, Nelson SG. Reliability of the Fugl-Meyer assessment of sensorimotor recovery following cerebrovascular accident. Phys Ther 1983;63:1606–1610.
    1. Sullivan KJ, Tilson JK, Cen SY, Rose DK, Hershberg J, Correa A. Fugl-Meyer assessment of sensorimotor function after stroke: standardized training procedure for clinical practice and clinical trials. Stroke 2011;42:427–432.
    1. Aizman I, Tirumalashetty BJ, McGrogan M, Case CC. Comparison of the neuropoietic activity of gene-modified versus parental mesenchymal stromal cells and the identification of soluble and extracellular matrix-related neuropoietic mediators. Stem Cell Res Ther 2014;5:29.
    1. Douketis JD, Spyropoulos AC, Spencer FA, et al. . Perioperative management of antithrombotic therapy: antithrombotic therapy and prevention of thrombosis. 9th ed. American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(suppl):e326S–e350S.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel