Safety and Efficacy of Riluzole in Acute Spinal Cord Injury Study (RISCIS): A Multi-Center, Randomized, Placebo-Controlled, Double-Blinded Trial

Abstract

Riluzole is a sodium-glutamate antagonist that attenuates neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favorable results in promoting recovery in pre-clinical models of traumatic spinal cord injury (tSCI) and in early phase clinical trials. This study aimed to evaluate the efficacy and safety of riluzole in acute cervical tSCI. An international, multi-center, prospective, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial (NCT01597518) was undertaken. Patients with American Spinal Injury Association Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 h from injury were randomized to receive either riluzole, at an oral dose of 100 mg twice per day (BID) for the first 24 h followed by 50 mg BID for the following 13 days, or placebo. The primary efficacy end-point was change in Upper Extremity Motor (UEM) scores at 180 days. The primary efficacy analyses were conducted on an intention to treat (ITT) and completed cases (CC) basis. The study was powered at a planned enrolment of 351 patients. The trial began in October 2013 and was halted by the sponsor on May 2020 (and terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the pre-planned enrolment) were randomized with a follow-up rate of 82.7% at 180 days. At 180 days, in the CC population the riluzole-treated patients compared with placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor scores (CI: -6.79-12.52). No drug-related serious adverse events were associated with the use of riluzole. Additional pre-planned sensitivity analyses revealed that in the AIS C population, riluzole was associated with significant improvement in total motor scores (estimate: standard error [SE] 8.0; CI 1.5-14.4) and upper extremity motor scores (SE 13.8; CI 3.1-24.5) at 6 months. AIS B patients had higher reported independence, measured by the Spinal Cord Independence Measure score (45.3 vs. 27.3; d: 18.0 CI: -1.7-38.0) and change in mental health scores, measured by the Short Form 36 mental health domain (2.01 vs. -11.58; d: 13.2 CI: 1.2-24.8) at 180 days. AIS A patients who received riluzole had a higher average gain in neurological levels at 6 months compared with placebo (mean 0.50 levels gained vs. 0.12 in placebo; d: 0.38, CI: -0.2-0.9). The primary analysis did not achieve the predetermined end-point of efficacy for riluzole, likely related to insufficient power. However, on pre-planned secondary analyses, all subgroups of cervical SCI subjects (AIS grades A, B and C) treated with riluzole showed significant gains in functional recovery. The results of this trial may warrant further investigation to extend these findings. Moreover, guideline development groups may wish to assess the possible clinical relevance of the secondary outcome analyses, in light of the fact that SCI is an uncommon orphan disorder without an accepted neuroprotective treatment.

Keywords: clinical trial; glutamate antagonist; neuroprotection; neurotrauma; sodium channel blocker; spinal cord injury.

FIG. 1.

Consolidated Standards of Reporting Trials (CONSORT) flow diagram of the Riluzole in Spinal Cord Injury Study (RISCIS) at the 180-day follow-up visit.

FIG. 2.

Changes in secondary and other end-points at 180 days from baseline in different baseline American Spinal Injury Association Impairment Scale subgroups in patients with traumatic cervical spinal cord injury randomized to either riluzole 100 mg oral dose twice per day (PO BID) for 24 h followed by 50 mg PO BID for 13 days after injury or placebo control. The p values were calculated using a one-tailed t-test with the alternative hypothesis being that the difference in scores is greater in the riluzole group. Analysis conducted on the complete cases population; n: 137.

FIG. 3.

Post hoc multi-variate linear regression of changes in Lower and Upper Extremity and Total International Standards for Neurological Classification of Spinal Cord Injury motor scores at 180 days compared with baseline with the administration of riluzole in different baseline American Spinal Injury Association Impairment Scale subgroups in patients with traumatic cervical spinal cord injury randomized to either riluzole 100 mg oral dose twice per day (PO BID) for 24 h followed by 50 mg PO BID for 13 days after injury or placebo controlled. Estimates represent the beta coefficient. Covariates used in the model include age, Charlson comorbidity Index, gender, neurological level of injury, and race. Analysis in the complete cases cohort; n: 137.