Riluzole in Spinal Cord Injury Study

Spinal Cord Injury Clinical Trial

— RISCIS  

Official title:

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01597518
• Other study ID #: SPN-12-001
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: October 2013
• Est. completion date: October 8, 2020

Study information

• Verified date: April 2021
• Source: AOSpine North America Research Network
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 193
• Est. completion date: October 8, 2020
• Est. primary completion date: October 8, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 75 Years

Eligibility

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 ß-human chorionic gonadotropin (ß-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

Related Conditions & MeSH terms

• Spinal Cord Injuries
• Spinal Cord Injury
• Wounds and Injuries

Intervention

Drug:
• Riluzole
100mg BID first 24 hours after the injury; 50mg BID 2--14 days following the injury
• Placebo
Placebo 2x in first 24 hours; Placebo 2x day 2--14

Locations

Country	Name	City	State
Australia	Royal Adelaide Hospital	Adelaide	South Australia
Australia	John Hunter Hospital	Newcastle	New South Wales
Australia	Prince of Wales Hospital	Randwick	New South Wales
Australia	Royal Rehab	Ryde	New South Wales
Australia	Royal North Shore Hospital	St Leonards	New South Wales
Canada	St. Michael's Hospital	Toronto	Ontario
Canada	Sunnybrook Health Sciences Centre	Toronto	Ontario
Canada	University of Toronto Hospital	Toronto	Ontario
Canada	University of British Columbia	Vancouver	British Columbia
United States	Emory University	Atlanta	Georgia
United States	University of Maryland	Baltimore	Maryland
United States	Louisiana State University	Baton Rouge	Louisiana
United States	University of Virginia	Charlottesville	Virginia
United States	University of Missouri	Columbia	Missouri
United States	Brooke Army Medical Center	Fort Sam Houston	Texas
United States	UT Health Center	Houston	Texas
United States	Kansas University Medical Center	Kansas City	Kansas
United States	University of Louisville	Louisville	Kentucky
United States	University of Wisconsin - Madison	Madison	Wisconsin
United States	University of Miami	Miami	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	Hospital of the University of Pennsylvania	Philadelphia	Pennsylvania
United States	Thomas Jefferson University	Philadelphia	Pennsylvania
United States	Barrow Neurological Institute	Phoenix	Arizona
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University	Saint Louis	Missouri
United States	University of Utah	Salt Lake City	Utah
United States	Santa Clara Valley Medical Center	San Jose	California
United States	Swedish Hospital	Seattle	Washington

Sponsors (5)

Lead Sponsor	Collaborator
AOSpine North America Research Network	AO Foundation, AO Spine, Christopher Reeve Paralysis Foundation, Rick Hansen Institute, United States Department of Defense

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

References & Publications (9)

Chow DS, Teng Y, Toups EG, Aarabi B, Harrop JS, Shaffrey CI, Johnson MM, Boakye M, Frankowski RF, Fehlings MG, Grossman RG. Pharmacology of riluzole in acute spinal cord injury. J Neurosurg Spine. 2012 Sep;17(1 Suppl):129-40. doi: 10.3171/2012.5.AOSPINE12 — View Citation

Fehlings MG, Nakashima H, Nagoshi N, Chow DS, Grossman RG, Kopjar B. Rationale, design and critical end points for the Riluzole in Acute Spinal Cord Injury Study (RISCIS): a randomized, double-blinded, placebo-controlled parallel multi-center trial. Spinal Cord. 2016 Jan;54(1):8-15. doi: 10.1038/sc.2015.95. Epub 2015 Jun 23. — View Citation

Fehlings MG, Wilson JR, Frankowski RF, Toups EG, Aarabi B, Harrop JS, Shaffrey CI, Harkema SJ, Guest JD, Tator CH, Burau KD, Johnson MW, Grossman RG. Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial. J Neurosurg Spine. 2012 Sep;17(1 Suppl):151-6. doi: 10.3171/2012.4.AOSPINE1259. — View Citation

Fehlings MG, Wilson JR, O'Higgins M. Introduction: Spinal cord injury at the cutting edge of clinical translation: a focus issue collaboration between NACTN and AOSpine North America. J Neurosurg Spine. 2012 Sep;17(1 Suppl):1-3. doi: 10.3171/2012.6.AOSPINE12632. — View Citation

Grossman RG, Fehlings MG, Frankowski RF, Burau KD, Chow DS, Tator C, Teng A, Toups EG, Harrop JS, Aarabi B, Shaffrey CI, Johnson MM, Harkema SJ, Boakye M, Guest JD, Wilson JR. A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury. J Neurotrauma. 2014 Feb 1;31(3):239-55. doi: 10.1089/neu.2013.2969. Epub 2013 Oct 11. — View Citation

Nagoshi N, Fehlings MG. Investigational drugs for the treatment of spinal cord injury: review of preclinical studies and evaluation of clinical trials from Phase I to II. Expert Opin Investig Drugs. 2015 May;24(5):645-58. doi: 10.1517/13543784.2015.1009629. Epub 2015 Feb 3. Review. — View Citation

Nagoshi N, Nakashima H, Fehlings MG. Riluzole as a neuroprotective drug for spinal cord injury: from bench to bedside. Molecules. 2015 Apr 29;20(5):7775-89. doi: 10.3390/molecules20057775. Review. — View Citation

Wilson JR, Fehlings MG. Riluzole for acute traumatic spinal cord injury: a promising neuroprotective treatment strategy. World Neurosurg. 2014 May-Jun;81(5-6):825-9. doi: 10.1016/j.wneu.2013.01.001. Epub 2013 Jan 4. Review. — View Citation

Wilson JR, Forgione N, Fehlings MG. Emerging therapies for acute traumatic spinal cord injury. CMAJ. 2013 Apr 2;185(6):485-92. doi: 10.1503/cmaj.121206. Epub 2012 Dec 10. Review. Erratum in: CMAJ. 2014 Mar 4;186(4):294. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in ISNCSCI Total Motor Score between 180 days and baseline		180 Days

External Links

•   AOSpine North America is a non for profit foundation for excellence in spine