The sodium-glutamate antagonist riluzole improves outcome after acute spinal cord injury: results from the RISCIS randomised controlled trial analysed using a global statistical analytic technique

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.

Keywords: Clinical trial; Global statistical test; Neuroprotection; Riluzole; Spinal cord injury.

Fig. 1

Flowchart diagram illustrating patient randomisation in the RISCIS trial andin the modified complete case series used in the current re-analysis.

Fig. 2

The boxplots for individual outcome scales (change from baseline to 6 months) compared between the placebo and riluzole group in the AIS A subgroup (n = 65). a) Total Motor Score (TOTM), b) Short Form Physical Component Score (SF-36 PCS), and c) Spinal Cord Independence Measure (SCIM). d) The boxplot representing the rank sum used for the GST analysis was added for comparative purposes. ∗p = 0.26 by student t-test, ∗∗p = 0.84 by student t-test, ∗∗∗p = 0.78 by student t-test, and ∗∗∗∗p = 0.02 by O'Brien modified t-test.

Fig. 3

Global treatment effect (GTE) stratified by AIS. GTE values (diamond figure) represent the probability of a good outcome in the riluzole group. The 95% confidence intervals of the GTE are represented by the limits of the coloured lines. The zero-dash line indicates no treatment effect (GTE = 0). The corresponding GTE p-values are provided in the annexed table.