Riluzole in Spinal Cord Injury Study

Overview

About this study

The aim of this study is to evaluate efficacy and safety of riluzole in the treatment of patients with acute SCI. The primary objective is to evaluate the superiority of riluzole, at a dose of 2 x 100 mg the first 24 hours followed by 2 x 50 mg for the following 13 days after injury, as compared to placebo, in change between 180 days and baseline in motor outcomes as measured by International Standards for Neurological Classification of Spinal Cord Injury Examination (ISNCSCI) Motor Score, in patients with acute traumatic SCI, presenting to the hospital less than 12 hours after injury. Secondary objectives are to evaluate the effects of riluzole on overall neurologic recovery, sensory recovery, functional outcomes, quality of life outcomes, health utilities, mortality, and adverse events. The working hypothesis is that the riluzole treated subjects will experience superior motor, sensory, functional, and quality of life outcomes as compared to those receiving placebo, with an acceptable safety profile.

Participation eligibility

Participant eligibility includes age, gender, type and stage of disease, and previous treatments or health concerns. Guidelines differ from study to study, and identify who can or cannot participate. There is no guarantee that every individual who qualifies and wants to participate in a trial will be enrolled. Contact the study team to discuss study eligibility and potential participation.

INCLUSION:

Age between 18 and 75 years inclusive
Able to cooperate in the completion of a standardized neurological examination by ISNCSCI standards (includes patients who are on a ventilator)
Willing and able to comply with the study Protocol
Signed Informed Consent Document (ICD) by patient, legal representative or witness
Able to receive the Investigational Drug within 12 hours of injury
ISNCSCI Impairment Scale Grade "A," "B" or "C" based upon first ISNCSCI evaluation after arrival to the hospital
Neurological Level of Injury between C4-C8 based upon first ISNCSCI evaluation after arrival to the hospital
Women of childbearing potential must have a negative serum β-human chorionic gonadotropin (β-hCG) pregnancy test or a negative urine pregnancy test
adults lacking capacity to consent

EXCLUSION:

Injury arising from penetrating mechanism
Significant concomitant head injury defined by a Glasgow Coma Scale score < 14 with a clinically significant abnormality on a head CT (head CT required only for patients suspected to have a brain injury at the discretion of the investigator)
Pre-existent neurologic or mental disorder which would preclude accurate evaluation and follow-up (i.e. Alzheimer's disease, Parkinson's disease, unstable psychiatric disorder with hallucinations and/or delusions or schizophrenia)
Previous history of spinal cord injury
Recent history (less than 1 year) of chemical substance dependency or significant psychosocial disturbance that may impact the outcome or study participation, in the opinion of the investigator
Is a prisoner
Participation in a clinical trial of another Investigational Drug or Investigational Device within the past 30 days
Hypersensitivity to riluzole or any of its components
Neutropenia measured as absolute neutrophil count (ANC) measured in cells per microliter of blood of < 1500 at screening visit
Creatinine level of > 1.2 milligrams (mg) per deciliter (dL) in males or > 1.1 mg per dL in females at screening visit
Liver enzymes (ALT/SGPT or AST/SGOT) 3 times the upper limit of normal (ULN) at screening visit
Active liver disease or clinical jaundice
Acquired immune deficiency syndrome (AIDS) or AIDS-related complex
Active malignancy or history of invasive malignancy within the last five years, with the exception of superficial basal cell carcinoma or squamous cell carcinoma of the skin that has been definitely treated. Patients with carcinoma in situ of the uterine cervix treated definitely more than 1 year prior to enrollment may enter the study
Lactating at screening visit
Subject is currently using, and will continue to use for the next 14 days any of the following medications which are classified as CYP1A2 inhibitors or inducers*:
Inhibitors:
- Ciprofloxacin
- Enoxacin
- Fluvoxamine
- Methoxsalen
- Mexiletine
- Oral contraceptives
- Phenylpropanolamine
- Thiabendazole
- Zileuton
Inducers:
- Montelukast
- Phenytoin

*Note: no washout period required; if these medications are discontinued, subjects are eligible to be enrolled in the trial

Participating Mayo Clinic locations

Study statuses change often. Please contact the study team for the most up-to-date information regarding possible participation.

Mayo Clinic Location	Status
Rochester, Minn. Mayo Clinic principal investigator Ahmad Nassr, M.D.	Closed for enrollment

Mayo Clinic Location

Status

Rochester, Minn.

Mayo Clinic principal investigator

Ahmad Nassr, M.D.

Closed for enrollment

More information

Publications

Riluzole is a sodium channel-blocking agent used in treating amyotrophic lateral sclerosis. It has been approved by the U.S. Food and Drug Administration, Canadian and Australian authorities, and in many other countries. A phase I trial of riluzole for acute spinal cord injury (SCI) provided safety and pharmacokinetic data and suggested neuroprotective benefits. A phase IIB/III double-blinded randomized controlled trial (RCT) started in January 2014 (https://clinicaltrials.gov, NCT01597518). This article describes the pathophysiological rationale, preclinical experience and design of the phase IIB/III RCT of Riluzole in Acute Spinal Cord Injury Study (RISCIS). Read More on PubMed
Efforts in basic research have clarified mechanisms involved in spinal cord injury (SCI), and resulted in positive findings using experimental treatments including cell transplantation and drug administration preclinically. Based on accumulated results, various clinical trials have begun for human SCI. Read More on PubMed
Spinal cord injury (SCI) is a devastating event resulting in permanent loss of neurological function. To date, effective therapies for SCI have not been established. With recent progress in neurobiology, however, there is hope that drug administration could improve outcomes after SCI. Riluzole is a benzothiazole anticonvulsant with neuroprotective effects. It has been approved by the U.S. Food and Drug Administration as a safe and well-tolerated treatment for patients with amyotrophic lateral sclerosis. The mechanism of action of riluzole involves the inhibition of pathologic glutamatergic transmission in synapses of neurons via sodium channel blockade. There is convincing evidence that riluzole diminishes neurological tissue destruction and promotes functional recovery in animal SCI models. Based on these results, a phase I/IIa clinical trial with riluzole was conducted for patients with SCI between 2010 and 2011. This trial demonstrated significant improvement in neurological outcomes and showed it to be a safe drug with no serious adverse effects. Currently, an international, multi-center clinical trial (Riluzole in Acute Spinal Cord Injury Study: RISCIS) in phase II/III is in progress with riluzole for patients with SCI (clinicaltrials.gov, registration number NCT01597518). This article reviews the pharmacology and neuroprotective mechanisms of riluzole, and focuses on existing preclinical evidence, and emerging clinical data in the treatment of SCI. Read More on PubMed
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. Read More on PubMed
In the immediate period after traumatic spinal cord injury (SCI) a variety of secondary injury mechanisms combine to gradually expand the initial lesion size, potentially leading to diminished neurological outcomes at long-term follow-up. Riluzole, a benzothiazole drug, which has neuroprotective properties based on sodium channel blockade and mitigation of glutamatergic toxicity, is currently an approved drug that attenuates the extent of neuronal degeneration in patients with amyotrophic lateral sclerosis. Moreover, several preclinical SCI studies have associated riluzole administration with improved functional outcomes and increased neural tissue preservation. Based on these findings, riluzole has attracted considerable interest as a potential neuroprotective drug for the treatment of SCI. Currently, a Phase I trial evaluating the safety and pharmacokinetic profile of riluzole in human SCI patients is being conducted by the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The current review summarizes the existing preclinical and clinical literature on riluzole, provides a detailed description of the Phase I trial, and suggests potential opportunities for future investigation. Clinical trial registration no.: NCT00876889. Read More on PubMed