By Michael Fehlings
Traumatic spinal cord injury results in major neurological impairment and loss of independence for the affected individual. Currently, over one million individuals in the USA and Canada live with the challenges of spinal cord injury. The lifetime economic impact of this injury is substantial and can be associated with costs exceeding several million dollars for an individual with traumatic tetraplegia. The past two decades have witnessed major advances in our knowledge of the pathophysiology of spinal cord injury. It is recognised that it involves an acute primary mechanical injury followed by a constellation of secondary injury events including ischaemia, sodium and calcium influx, glutamatergic excitotoxicity, inflammation and delayed cellular apoptosis. This knowledge has contributed to improvements in medical, surgical and rehabilitation treatments. For example, the recently completed STASCIS1 (Surgical timing in acute spinal cord injury study) demonstrated improved outcomes with early decompression for cervical spinal cord injury. However, despite a number of well-conducted clinical trials in the past—including the National acute spinal cord injury study (NASCIS) and the studies on Sygen (Fidia)—no drug has been convincingly shown to attenuate the impact of the acute traumatic injury to the cord.
On a more positive note, recent advances in the pathobiology of spinal cord injury have identified several promising strategies to mitigate the effects of secondary pathology following acute traumatic injury to the cord. Among these strategies, the sodium-glutamate antagonist riluzole holds particular promise. This drug is FDA-approved to attenuate nerve cell degeneration in the patients with amyotrophic lateral sclerosis and has shown very promising results in preclinical models of traumatic and ischaemic spinal cord injury. Significantly, investigators supported by AOSpine North America (Fehlings et al) are currently conducting a multicentre randomised controlled clinical trial evaluating the perioperative use of riluzole as a neuroprotective agent in patients undergoing surgery for cervical spondylotic myelopathy. Furthermore, riluzole is also being assessed as a neuroprotective agent for patients with spinal cord injury.
In a phase I/IIa study2, 36 patients with acute spinal cord injury (American Spinal Injury Association [ASIA] score A-C; 28 cervical, eight thoracic) received riluzole (50mg twice a day) within 12 hours of injury. The outcomes were compared with a prospective matched cohort of patients from the North American clinical trials network (NACTN) registry. Complications were similar in the riluzole and control groups, with a trend for reduced cardiovascular complications in patients receiving riluzole. Promising rates of neurological recovery were observed in the spinal cord injury patients receiving the drug—particularly those with cervical spinal cord injury, where significant improvements were observed in ASIA motor score recovery at three months.
Based on these results and a compelling clinical and preclinical track record, a consortium (supported by AOSpine North America, NACTN and AOSpine International) is launching a prospective, multicentre, randomised controlled trial evaluating the therapeutic benefit of riluzole vs. placebo on neurological outcomes in patients with acute cervical spinal cord injury (Riluzole in spinal cord injury study; RISCIS). The study, which has received clearance from FDA and Health Canada, is expected to begin enrolling patients early in the fall [autumn]—with a planned enrolment of 350 patients. The study will employ a sequential adaptive design and will incorporate one interim analysis at 60% enrolment with a potential sample size adjustment incorporated into the methodological design.
While it will take three to four years to complete the RISCIS study; if successful, this trial could lead to a safe, effective neuroprotective drug into the clinical management of patients with acute spinal cord injury.
For more information, see the RISCIS trial description here.
Representing a team of investigators supported by the North American Clinical Trials Network (NACTN; supported by the Christopher and Dana Reeve Foundation through a US Department of Defense grant) and AOSpine (North America and International), Michael Fehlings spoke about RISCIS at IMAST
He is the principal investigator of the RISCIS trial, chairman of AOSpine North America, and professor of Neurosurgery, University of Toronto, Halbert Chair in Neural Repair and Regeneration; and medical director, Krembil Neuroscience Centre, Toronto Western Hospital, Toronto, Canada
1. Fehlings et al. PloS One 2012. Epub
2. Grossman et al. Journal of Neurotrauma 2013. Epub