A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury

Abstract

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group.

Figures

FIG. 1.

Patient flow diagram of numbers of riluzole and registry patients available with complete motor scores on admission and at 42, 90, and 180 days.

FIG. 2.

Cervical and thoracic injuries: frequency of normal and elevated liver enzymes and bilirubin. See Table 10. ALT, alanine transferase; AST, aspartate transamine; ALP, alkaline phosphatase; GGT, gamma-glutamyl transpeptidase; RZ, riluzole.

FIG. 3.

Cervical injuries: riluzole and registry patients. Progression of mean total motor score (and n patients available) at admission and 42, 90, and 180 days, stratified by admission impairment grade. (A) All grades. (B) Grade A. (C) Grade B. (D) Grade C. See Table 11.

FIG. 4.

Cervical injuries: riluzole and registry patients. Box plots of gains in total motor score. (A) 90 days. (B) 180 days. max, min, maximal and minimal scores encompassing at least 99% of the data; p25, p75, 25th and 75th percentiles.

FIG. 5.

Cervical injuries: riluzole and registry patients. Box plots of gains in pin-prick scores, all grades. (A) 90 days. (B) 180 days. max, min, maximal and minimal scores encompassing at least 99% of the data; •max, •min, outlying values; p25, p75, 25th and 75th percentiles.