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. 2018 May 1;35(9):1049-1056.
doi: 10.1089/neu.2017.5434. Epub 2018 Mar 1.

Rho Inhibitor VX-210 in Acute Traumatic Subaxial Cervical Spinal Cord Injury: Design of the SPinal Cord Injury Rho INhibition InvestiGation (SPRING) Clinical Trial

Michael G Fehlings  1 , Kee D Kim  2 , Bizhan Aarabi  3 , Marco Rizzo  4 , Lisa M Bond  5 , Lisa McKerracher  5 , Alexander R Vaccaro  6 , David O Okonkwo  7
Affiliations

Rho Inhibitor VX-210 in Acute Traumatic Subaxial Cervical Spinal Cord Injury: Design of the SPinal Cord Injury Rho INhibition InvestiGation (SPRING) Clinical Trial

Michael G Fehlings et al. J Neurotrauma. .

Abstract

Traumatic spinal cord injury (SCI) is associated with a lifetime of disability stemming from loss of motor, sensory, and autonomic functions; these losses, along with increased comorbid sequelae, negatively impact health outcomes and quality of life. Early decompression surgery post-SCI can enhance patient outcomes, but does not directly facilitate neural repair and regeneration. Currently, there are no U.S. Food and Drug Administration-approved pharmacological therapies to augment motor function and functional recovery in individuals with traumatic SCI. After an SCI, the enzyme, Rho, is activated by growth-inhibitory factors and regulates events that culminate in collapse of the neuronal growth cone, failure of axonal regeneration, and, ultimately, failure of motor and functional recovery. Inhibition of Rho activation is a potential treatment for injuries such as traumatic SCI. VX-210, an investigational agent, inhibits Rho. When administered extradurally after decompression (corpectomy or laminectomy) and stabilization surgery in a phase 1/2a study, VX-210 was well tolerated. Here, we describe the design of the SPRING trial, a multicenter, phase 2b/3, randomized, double-blind, placebo-controlled clinical trial to evaluate the efficacy and safety of VX-210 (NCT02669849). A subset of patients with acute traumatic cervical SCI is currently being enrolled in the United States and Canada. Medical, neurological, and functional changes are evaluated at 6 weeks and at 3, 6, and 12 months after VX-210 administration. Efficacy will be assessed by the primary outcome measure, change in upper extremity motor score at 6 months post-treatment, and by secondary outcomes that include question-based and task-based evaluations of functional recovery.

Keywords: Rho inhibition; SPRING trial; VX-210; motor recovery; spinal cord injury.

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Conflict of interest statement

Kee D. Kim has served on steering committees for spinal cord injury trials for Vertex Pharmaceuticals Incorporated and InVivo Therapeutics. Lisa M. Bond is an employee of BioAxone Biosciences, Inc, and may hold stock and/or stock options in the company and has received consulting fees from Vertex Pharmaceuticals Incorporated. Lisa McKerracher is an employee of BioAxone Biosciences, Inc, and has three issued patents licensed to Vertex Pharmaceuticals Incorporated (US7141428, US6855688, and US7795218). Marco Rizzo is an employee of Vertex Pharmaceuticals Incorporated and may hold stock and/or stock options in the company. Alexander R. Vaccaro holds stock and/or stock options in Replication Medica, Globus, Paradigm Spine, Stout Medical, Progressive Spinal Technologies, Advanced Spinal Intellectual Properties, Spine Medica, Computational Biodynamics, Spinology, Flagship Surgical, Cytonics, Bonovo Orthopaedics, Electrocore, Gamma Spine, FlowPharma, Rothman Institute and Related Properties, Innovative Surgical Design, Vertiflex, Avaz Surgical, Prime Surgeons, Dimension Orthotics, LLC, Vexim, SpineWave, Atlas Spine, Insight Therapeutics, Nuvasive, and Parvizi Surgical Innovation; has received consulting fees or royalties from DePuy, Medtronics, Stryker Spine, Globus, Stout Medical, Aesculap, Gerson Lehrman Group, Guidepoint Global, Medacorp, Innovative Surgical Design, Orthobullets, Thieme, Jaypee, Elsevier, Taylor Francis/Hodder and Stoughton, Expert Testimony, Vexim, SpineWave, Atlas Spine, and Nuvasive; is a board member of Progressive Spinal Technologies, Flagship Surgical, AO Spine, Innovative Surgical Design, Prime Surgeons, Spine Therapy Network, Inc, and Parvizi Surgical Innovation; and serves as an editor for Clinical Spine Surgery and Spine Journal. Michael G. Fehlings, Bizhan Aarabi, and David O. Okonkwo have no conflicts of interest to disclose.

Aspects of the original study design for this trial were presented, in part, at the 34th Annual National Neurotrauma Symposium, June 26–29, 2016, Lexington, Kentucky.

Figures

<b>FIG. 1.</b>
FIG. 1.
SCI-mediated Rho (A) activation and (B) inhibition by VX-210. CSPG, chondroitin sulfate proteoglycan; MAG, myelin-associated glycoprotein; Nogo-A, neurite outgrowth inhibitory protein A; OMgp, oligodendrocyte-myelin glycoprotein; RGM, repulsive guidance molecule; TNF, tumor necrosis factor.
<b>FIG. 2.</b>
FIG. 2.
Penetration of VX-210 into spinal cord tissue. (A) Extradural administration and penetration into spinal cord tissue. (B) VX-210 relative penetration into spinal cord tissue in a post-mortem pig model after administration of a 1-mg dose. SCI, spinal cord injury.
<b>FIG. 3.</b>
FIG. 3.
Study design of the phase 2b/3 SPRING trial. AIS, American Spinal Injury Association Impairment Scale; SCI, spinal cord injury. aApplication of VX-210/placebo occurs during decompression/stabilization surgery. bAll post-treatment follow-up dates occur within ±7 days.
See this image and copyright information in PMC

References

    1. National Spinal Cord Injury Statistical Center. Spinal cord injury facts and figures at a glance. 2017. Available at: https://www.nscisc.uab.edu Accessed July14, 2017
    1. Singh A., Tetreault L., Kalsi-Ryan S., Nouri A., and Fehlings M.G. (2014). Global prevalence and incidence of traumatic spinal cord injury. Clin. Epidemiol. 6, 309–331 - PMC - PubMed
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    1. World Health Organization. Spinal cord injury: fact sheet no. 384. 2013. Available at: http://www.who.int/mediacentre/factsheets/fs384/en/ Accessed July14, 2017
    1. Fehlings M.G., Vaccaro A., Wilson J.R., Singh A., Cadotte D.W., Harrop J.S, Aarabi B., Shaffrey C., Dvorak M., Fisher C., Arnold P., Massicotte E.M., Lewis S., and Rampersaud R. (2012). Early versus delayed decompression for traumatic cervical spinal cord injury: results of the surgical timing in acute spinal cord injury study (STASCIS). PLoS One 7, e32037. - PMC - PubMed

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