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• W4386021787 abstract "BACKGROUND CONTEXT Riluzole is sodium-glutamate antagonist used to attenuate neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favourable results in promoting neural recovery in preclinical models of traumatic spinal cord injury (tSCI) with early phase clinical results suggesting enhanced neurological outcomes. PURPOSE This study aimed to evaluate the efficacy and safety of riluzole in patients with acute cervical tSCI. STUDY DESIGN/SETTING A prospective, international, multi-center, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial was undertaken. PATIENT SAMPLE Patients with ASIA Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 hours from injury. OUTCOME MEASURES The primary efficacy endpoint was change in Upper Extremity Motor (UEM) scores at 180 days from baseline. Secondary objectives were to evaluate the effects of riluzole on overall neurologic recovery, sensory recovery, functional outcomes, quality of life outcomes, health utilities, mortality, and adverse events. METHODS Participants were randomized to receive either riluzole, at an oral dose of 100mg twice per day (BID) for the first 24 hours followed by 50mg BID for the following 13 days, or a placebo. The primary efficacy analyses were conducted on an intention-to-treat (ITT) and completed cases (CC) basis. The appropriate statistical approach was to test a single one-sided null hypothesis that the difference between the investigational and the placebo arm was equal to or less than 0. Testing for all secondary outcomes will be based on appropriate statistical methods and two-way superiority testing RESULTS The trial began enrollment in October 2013 and was halted by the sponsor on May 2020 (and ultimately terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the preplanned 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 to placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor (TOTM) scores (CI:-6.79-12.52). In the AIS B patients there was a statistically significant gain in the spinal cord independence measure: 45.3 vs 27.3 (d: 18.0 CI: -1.7-38.0). In the AIS A population, patients in the riluzole subgroup on average had 0.50 neurological levels gained at 180-days compared to 0.12 levels in the placebo group. In the AIS C subgroup, the administration of riluzole was associated with an increase in upper motor (SE 8.0; CI 1.5-14.4) change at 180-days compared to placebo in multivariate linear regression. No drug-related serious adverse events were associated with the use of riluzole. CONCLUSIONS While the gain in UEM scores seen with riluzole does not reach the prespecified statistical criteria for superiority, there is strong suggestive evidence in favor of riluzole from preplanned secondary analyses in every subgroup. The results warrant further investigation from guideline development groups related to the management of tSCI. FDA Device/Drug Status Riluzole (Not approved for this indication) Riluzole is sodium-glutamate antagonist used to attenuate neurodegeneration in amyotrophic lateral sclerosis (ALS). It has shown favourable results in promoting neural recovery in preclinical models of traumatic spinal cord injury (tSCI) with early phase clinical results suggesting enhanced neurological outcomes. This study aimed to evaluate the efficacy and safety of riluzole in patients with acute cervical tSCI. A prospective, international, multi-center, randomized, double-blinded, placebo-controlled, adaptive, Phase III trial was undertaken. Patients with ASIA Impairment Scale (AIS) A-C, cervical (C4-C8) tSCI, and <12 hours from injury. The primary efficacy endpoint was change in Upper Extremity Motor (UEM) scores at 180 days from baseline. Secondary objectives were to evaluate the effects of riluzole on overall neurologic recovery, sensory recovery, functional outcomes, quality of life outcomes, health utilities, mortality, and adverse events. Participants were randomized to receive either riluzole, at an oral dose of 100mg twice per day (BID) for the first 24 hours followed by 50mg BID for the following 13 days, or a placebo. The primary efficacy analyses were conducted on an intention-to-treat (ITT) and completed cases (CC) basis. The appropriate statistical approach was to test a single one-sided null hypothesis that the difference between the investigational and the placebo arm was equal to or less than 0. Testing for all secondary outcomes will be based on appropriate statistical methods and two-way superiority testing The trial began enrollment in October 2013 and was halted by the sponsor on May 2020 (and ultimately terminated in April 2021) in the face of the global COVID-19 pandemic. One hundred ninety-three patients (54.9% of the preplanned 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 to placebo had a mean gain of 1.76 UEM scores (95% confidence interval: -2.54-6.06) and 2.86 total motor (TOTM) scores (CI:-6.79-12.52). In the AIS B patients there was a statistically significant gain in the spinal cord independence measure: 45.3 vs 27.3 (d: 18.0 CI: -1.7-38.0). In the AIS A population, patients in the riluzole subgroup on average had 0.50 neurological levels gained at 180-days compared to 0.12 levels in the placebo group. In the AIS C subgroup, the administration of riluzole was associated with an increase in upper motor (SE 8.0; CI 1.5-14.4) change at 180-days compared to placebo in multivariate linear regression. No drug-related serious adverse events were associated with the use of riluzole. While the gain in UEM scores seen with riluzole does not reach the prespecified statistical criteria for superiority, there is strong suggestive evidence in favor of riluzole from preplanned secondary analyses in every subgroup. The results warrant further investigation from guideline development groups related to the management of tSCI." @default.
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• W4386021787 date "2023-09-01" @default.
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• W4386021787 title "69. Safety and efficacy of riluzole in acute spinal cord injury (RISCIS): a multicenter, randomized, placebo-controlled, double-blinded trial" @default.
• W4386021787 doi "https://doi.org/10.1016/j.spinee.2023.06.121" @default.
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