Riluzole in Spinal Cord Injury Study (RISCIS)

April 16, 2021 updated by: AOSpine North America Research Network

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

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.

Study Overview

Status

Terminated

Conditions

Intervention / Treatment

Detailed Description

At present there are over 1 million people living with Spinal Cord Injury (SCI) in North America alone, with annual costs for the acute treatment and chronic care of these patients totaling four billion dollars USD. The worldwide prevalence of SCI is unknown, with estimates ranging up to 250 million individuals. The incidence of SCI in developed countries has been estimated to be between 10 - 40 cases per million inhabitants. In spite of the immense impact of SCI at a personal and societal level, an effective and safe pharmacologic treatment for SCI, shown to improve neurological and functional outcomes at long-term follow-up, remains absent.

The final degree of neurological tissue destruction that occurs after traumatic SCI is a product of both primary and secondary injury mechanisms. The primary mechanical injury to the cord initiates a subsequent signaling cascade of deleterious down-stream events, known collectively as secondary injury mechanisms. These secondary injury mechanisms include ischemia, interstitial and cellular ionic imbalance, free radical formation, glutamatergic excitotoxicity, lipid peroxidation and generation of arachidonic acid metabolites. Although little can be done from a therapeutic standpoint to correct damage sustained during the primary injury, by mitigating the evolution of secondary injury events there is opportunity to preserve remnant viable neurological tissue and improve neurologic outcomes. There is convincing evidence from the preclinical realm that the pharmacologic agent riluzole attenuates certain aspects of the secondary injury cascade leading to diminished neurological tissue destruction in animal SCI models. Riluzole, a sodium channel blocking benzothiazole anticonvulsant, specifically exerts its neuroprotective effect by helping to maintain neuronal cellular ionic balance and by reducing the release of excitotoxic glutamate in the post-SCI setting. Several preclinical studies in the rodent SCI model have associated administration of riluzole with increased neural tissue preservation at the site of injury, in addition to improved behavioral outcomes, in comparison to administration of placebo or other sodium channel blocking drugs. In the clinical realm, while riluzole has not been studied extensively in the context of SCI, it has been widely used in the treatment of amyotrophic lateral sclerosis (ALS). A 2007 Cochrane review, summarizing the findings of 4 placebo-controlled randomized trials, concluded that at a dose of 100 mg daily, riluzole is safe and improves median survival by 2-3 months in patients with ALS. In regards to adverse events (AEs), riluzole was well tolerated, although treated patients were 2.6 times more likely to experience a three-fold increase in serum alanine transaminase (ALT) as compared to patients treated with placebo. However, this effect was found to be uniformly reversible with cessation of riluzole therapy and was only reported after several months of medication administration. Recently, the clinical safety and pharmacokinetic profile of riluzole have been studied in a multi-center pilot study in the context of traumatic SCI. A total of 36 patients received an oral dose of riluzole 50 mg twice daily for 2 weeks, with treatment initiated within 12 hours of injury for all patients. The 12 hour dosing window, as well as the 2 week duration of therapy, was chosen to match the period of medication administration to the known period of glutamatergic excitotoxicity after SCI (several minutes after injury until 2 weeks after injury). With the final analysis currently undergoing peer review, completion of this study has confirmed the acceptable safety profile of riluzole administration previously documented in the ALS literature, and has established the feasibility of conducting a large-scale efficacy trial investigating this therapy.

At present, there is no specific pharmacological therapy that is given uniformly to all patients with traumatic SCI. As a result, a placebo-controlled comparison group is ethical and justifiable.

The aim of the current trial is to evaluate efficacy and safety of riluzole in the treatment of patients with acute SCI.

The primary objective of the current Phase II/III trial 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.

Study Type

Interventional

Enrollment (Actual)

193

Phase

  • Phase 2
  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Australia
    • New South Wales
      • Newcastle, New South Wales, Australia, 2310
        • John Hunter Hospital
      • Randwick, New South Wales, Australia, 2031
        • Prince of Wales Hospital
      • Ryde, New South Wales, Australia, 2112
        • Royal Rehab
      • St Leonards, New South Wales, Australia, 2065
        • Royal North Shore Hospital
    • South Australia
      • Adelaide, South Australia, Australia, 5000
        • Royal Adelaide Hospital
  • Canada
    • British Columbia
      • Vancouver, British Columbia, Canada, V5Z 1M9
        • University of British Columbia
    • Ontario
      • Toronto, Ontario, Canada, M4N 3M5
        • Sunnybrook Health Sciences Centre
      • Toronto, Ontario, Canada, M5T 2S8
        • University of Toronto Hospital
      • Toronto, Ontario, Canada, M5R 1C6
        • St. Michael's Hospital
  • United States
    • Arizona
      • Phoenix, Arizona, United States, 85013
        • Barrow Neurological Institute
    • California
      • San Jose, California, United States, 95128
        • Santa Clara Valley Medical Center
    • Florida
      • Miami, Florida, United States, 33136
        • University of Miami
    • Georgia
      • Atlanta, Georgia, United States, 30303
        • Emory University
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • Kansas University Medical Center
    • Kentucky
      • Louisville, Kentucky, United States, 40202
        • University of Louisville
    • Louisiana
      • Baton Rouge, Louisiana, United States, 70803
        • Louisiana State University
    • Maryland
      • Baltimore, Maryland, United States, 21201
        • University of Maryland
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
    • Missouri
      • Columbia, Missouri, United States, 65212
        • University of Missouri
      • Saint Louis, Missouri, United States, 63110
        • Washington University
    • Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19104
        • Hospital of the University of Pennsylvania
      • Philadelphia, Pennsylvania, United States, 19107
        • Thomas Jefferson University
    • Texas
      • Fort Sam Houston, Texas, United States, 78234
        • Brooke Army Medical Center
      • Houston, Texas, United States, 77030
        • UT Health Center
    • Utah
      • Salt Lake City, Utah, United States, 84112
        • University of Utah
    • Virginia
      • Charlottesville, Virginia, United States, 22908
        • University of Virginia
    • Washington
      • Seattle, Washington, United States, 98122
        • Swedish Hospital
    • Wisconsin
      • Madison, Wisconsin, United States, 53706
        • University of Wisconsin - Madison
      • Milwaukee, Wisconsin, United States, 53226
        • Medical College of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 75 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Placebo Comparator: Placebo
Drug: Placebo
Placebo 2x in first 24 hours; Placebo 2x day 2--14
Experimental: Riluzole
Drug: Riluzole
100mg BID first 24 hours after the injury; 50mg BID 2--14 days following the injury

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
Change in ISNCSCI Total Motor Score between 180 days and baseline
Time Frame: 180 Days
180 Days

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

AOSpine North America Research Network

Collaborators

United States Department of Defense
Rick Hansen Institute
Christopher Reeve Paralysis Foundation
AO Foundation, AO Spine

Investigators

  • Principal Investigator: Michael Fehlings, MD, PhD, University Health Network, Toronto, Canada
  • Study Director: Branko Kopjar, MD, PhD, University of Washington

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

October 1, 2013

Primary Completion (Actual)

October 8, 2020

Study Completion (Actual)

October 8, 2020

Study Registration Dates

First Submitted

May 10, 2012

First Submitted That Met QC Criteria

May 11, 2012

First Posted (Estimate)

May 14, 2012

Study Record Updates

Last Update Posted (Actual)

April 19, 2021

Last Update Submitted That Met QC Criteria

April 16, 2021

Last Verified

April 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • SPN-12-001

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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