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.

Background: Traumatic brachial plexus injuries (BPIs) disproportionately affect young, able-bodied individuals. Beyond direct costs associated with medical treatment, there are far-reaching indirect costs related to disability and lost productivity. Our objective was to estimate per-patient indirect cost associated with BPI. Methods: We estimated indirect costs as the sum of (1) short-term wage loss, (2) long-term wage loss, and (3) disability payments. Short-term (6-month) wage loss was the product of missed work days and the average earnings per day. The probability of return to work was derived from a systematic review of the literature, and long-term wage loss and disability payments were estimated. Monte Carlo simulation was used to perform a sensitivity analysis of long-term wage loss by varying age, sex, and return to work simultaneously. Disability benefits were estimated from U.S. Social Security Administration data. All cost estimates are in 2018 U.S. dollars. Results: A systematic review of the literature demonstrated that the patients with BPI had a mean age of 26.4 years, 90.5% were male, and manual labor was the most represented occupation. On the basis on these demographics, our base case was a 26-year-old American man working as a manual laborer prior to BPI, with an annual wage of $36,590. Monte Carlo simulation estimated a short-term wage loss of $22,740, a long-term wage loss of $737,551, and disability benefits of $353,671. The mean total indirect cost of traumatic BPI in the Monte Carlo simulations was $1,113,962 per patient over the post-injury lifetime (median: $801,723, interquartile range: $22,740 to $2,350,979). If the probability of the patient returning to work at a different, lower-paying job was doubled, the per-patient total indirect cost was $867,987. Conclusions: BPI can have a far-reaching economic impact on both individuals and society. If surgical reconstruction enables patients with a BPI to return to work, the indirect cost of this injury decreases. Level of Evidence: Economic Level IV. See Instructions for Authors for a complete description of levels of evidence.