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.
Highlights
Acute spinal cord injuryCurrent estimates indicate that 245,000–353,000 individuals who have suffered a spinal cord injury (SCI) are living in the United States, and approximately 40–54 new cases per year per million individuals occur.[1,2] Common causes of SCI in the United States are motor vehicle accidents (38–42%), falls (31–33%), sports injuries (9–16%), and violence/other (9–18%).[1,3] Worldwide, the estimated incidence of SCI ranges from 250,000–500,000 individuals per year,[4] and approximately 2.5 million people live with an SCI.[3]SCIs are often attributed to spinal cord compression and contusion that occur within a fraction of a second.[5]
Primary damage to the spinal cord is caused by the physical trauma, and further injury is caused by downstream pathophysiological signaling cascades.[6]. This secondary damage is propagated through several mechanisms of action, including ischemia, excitotoxicity, 1Division of Neurosurgery and Spine Program, University of Toronto, Toronto, Ontario, Canada. 2Department of Neurological Surgery, University of California Davis School of Medicine, Sacramento, California. 3Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland. 4Vertex Pharmaceuticals Incorporated, Boston, Massachusetts. 5BioAxone BioSciences, Inc, Cambridge, Massachusetts. 6Department of Orthopaedic Surgery, Sidney Kimmel Medical Center at Thomas Jefferson University, Philadelphia, Pennsylvania. 7Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania
The results suggested improvement in motor strength in patients with cervical SCI compared to patients in natural history studies.[28]
Summary
Current estimates indicate that 245,000–353,000 individuals who have suffered a spinal cord injury (SCI) are living in the United States, and approximately 40–54 new cases per year per million individuals occur.[1,2] Common causes of SCI in the United States are motor vehicle accidents (38–42%), falls (31–33%), sports injuries (9–16%), and violence/other (9–18%).[1,3] Worldwide, the estimated incidence of SCI ranges from 250,000–500,000 individuals per year,[4] and approximately 2.5 million people live with an SCI.[3]. A recognized standard of care for traumatic SCI is immediate immobilization, prevention of neurogenic shock, intubation, oxygenation, imaging evaluation, reduction, decompression, and stabilization These measures, which help relieve direct pressure on the spinal cord and ischemic hypoxia, may reduce secondary damage.[5,22,23] treatment of an acute SCI with decompression and stabilization surgery may provide clinical benefit to patients, this procedure does not directly facilitate axonal regeneration and repair.[3] The primary goal of acute therapy for SCI is restoration of sufficient motor function to increase autonomy. In rodent models of neuronal injury, treatment with VX-210 reversed the activation of Rho in spinal cord lesions, decreased
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