Michael G. Fehlings, University of Toronto, ON, Canada
Karlo M. Pedro, University of Toronto, ON, Canada
Mohammed Ali Alvi, University of Toronto, ON, Canada
Ali Moghaddamjou, University of Toronto, ON, Canada
James S. Harrop, Thomas Jefferson University, Philadelphia, PA
Ralph Stanford, Prince of Wales Hospital, Sydney, Australia
Jonathon Ball, Royal North Shore Hospital, St. Leonards, New South Wales, Australia
Bizhan Aarabi, University of Maryland, Baltimore, MD
Paul M. Arnold, University of Illinois Urbana-Champaign, Champaign, IL
James D. Guest, University of Miami, Miami, FL
Shekar N. Kurpad, Medical College of Wisconsin, Wauwatosa, WI
James M. Schuster, University of Pennsylvania Health System, Philadelphia, PA
Ahmad N. Nassr, Mayo Clinic, Rochester, MN
Karl M. Schmitt, University of Texas, Houston, TX
Jefferson R. Wilson, University of Toronto, ON, Canada
Darrel S. Brodke, University of Utah, Salt Lake City, UT
Faiz U. Ahmad, Emory University School of Medicine, Atlanta, GA
Albert Yee, University of Toronto, Toronto, ON, Canada
Wilson Z. Ray, Washington University School of Medicine in St. Louis
Nathaniel P. Brooks, University of Wisconsin School of Medicine and Public Health, Madison, WI
Jason Wilson, LSU Health Sciences Center - New OrleansFollow
Diana S.L. Chow, University of Houston, Houston, TX
Elizabeth G. Toups, Houston Methodist Hospital, Houston, TX
Kevin E. Thorpe, University of Toronto, Toronto, ON, Canada
Jiaxin Huang, Johns Hopkins University, Baltimore, MD
Peng Huang, Johns Hopkins University, Baltimore, MD

Document Type

Article

Publication Date

7-24-2025

Publication Title

eBioMedicine

Abstract

Background: Spinal cord injury (SCI) clinical trials typically rely on a single primary endpoint to assess drug efficacy. This strategy fails to adequately capture the full impact of treatment in heterogenous neurological conditions like SCI. A more patient-centric analysis requires assessment of neurological function, functional capacity, and quality of life, incorporating meaningful patient-reported outcomes. The global statistical test (GST) addresses this challenge using a unified statistical conclusion regarding the superiority of a treatment strategy over another by evaluating multiple trial endpoints simultaneously. Methods: The RISCIS trial (Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study) data was analysed using a multivariate nonparametric GST, integrating the total American Spinal Injury Association (ASIA) motor score (TOTM), Spinal Cord Independence Measure (SCIM), and SF-36 PCS (Short Form-36 Physical Component Scale) scores. In the RISCIS trial, patients with severe cervical SCI (AIS A, B, and C) were randomised to receive riluzole or placebo within 12 h of injury in a double blinded fashion. We compared six-month outcomes between groups using a modified O'Brien's rank sum test with sample variance adjustment. Higher summed ranks represent better global outcomes. The overall probability of improvement was computed using a summary estimate, the global treatment effect (GTE). Findings: A total of 131 patients (mean age 45.8 years old, 82% males) completed the six-month outcome assessment. Among these, 49.6% were classified as AIS A, 20.6% as AIS B, and 29% as AIS C. Riluzole was administered within 12 h from injury for 14 days in 65 patients, while 66 received a placebo. The unadjusted mean change from baseline to six months showed a favourable response in the riluzole group compared to placebo across TOTM (p = 0.28 by t-test; p = 0.26 by Wilcoxon test), SCIM (p = 0.04 by t-test; p = 0.02 by Wilcoxon test), or SF-36 PCS (p = 0.23 by t-test; p = 0.21 by Wilcoxon test) scores. Using the GST to simultaneously assess these measures, the riluzole group exhibited a higher rank sum compared to placebo [median rank sum = 207 (IQR: 166–246) in riluzole vs 185 (IQR: 146–236) in placebo, p = 0.04]. Subgroup analysis revealed the greatest treatment benefit among patients with AIS A injuries (GTE = 0.16, 95% CI: 0.01–0.31, p = 0.02). At six months, the probability that riluzole treatment resulted in overall better outcomes than placebo across all assessed outcomes was 58%. Interpretation: Riluzole was associated with improved global outcomes in patients with severe traumatic SCI, based on a composite score integrating ASIA total motor scores, SCIM, and SF36 outcomes at six months. Riluzole is a promising therapeutic option in SCI, but further investigation through higher-quality studies incorporating multidimensional assessments is warranted. Funding: No funding was received for the present work. The original clinical trial (NCT01597518) was funded by the AO Foundation, United States Department of Defense (DOD), and the Praxis Spinal Cord Institute.

PubMed ID

40712181

Volume

118

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