Clinical trial NCT01597518: Riluzole in Spinal Cord Injury Study
Official title: A Multi-Center, Randomized, Placebo Controlled, Double-Blinded, Trial of Efficacy and Safety of Riluzole in Acute Spinal Cord Injury
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Spinal Cord Injury
Keywords: Riluzole
spinal cord injury
treatment
Lead sponsor: AOSpine North America Research Network
Sponsor class: NETWORK
Collaborators: name: AO Foundation, AO Spine
name: United States Department of Defense
name: Rick Hansen Institute
name: Christopher Reeve Paralysis Foundation
First posted: 2012-05-14
Enrollment: 193
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in ISNCSCI Total Motor Score between 180 days and baseline
timeFrame: 180 Days
Secondary outcomes:
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Barrow Neurological Institute
state: Arizona
city: San Jose
country: United States
facility: Santa Clara Valley Medical Center
state: California
city: Miami
country: United States
facility: University of Miami
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Kansas City
country: United States
facility: Kansas University Medical Center
state: Kansas
city: Louisville
country: United States
facility: University of Louisville
state: Kentucky
city: Baton Rouge
country: United States
facility: Louisiana State University
state: Louisiana
city: Baltimore
country: United States
facility: University of Maryland
state: Maryland
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Columbia
country: United States
facility: University of Missouri
state: Missouri
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Philadelphia
country: United States
facility: Hospital of the University of Pennsylvania
state: Pennsylvania
city: Philadelphia
country: United States
facility: Thomas Jefferson University
state: Pennsylvania
city: Fort Sam Houston
country: United States
facility: Brooke Army Medical Center
state: Texas
city: Houston
country: United States
facility: UT Health Center
state: Texas
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
city: Seattle
country: United States
facility: Swedish Hospital
state: Washington
city: Madison
country: United States
facility: University of Wisconsin - Madison
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Randwick
country: Australia
facility: Prince of Wales Hospital
state: New South Wales
city: Ryde
country: Australia
facility: Royal Rehab
state: New South Wales
city: St Leonards
country: Australia
facility: Royal North Shore Hospital
state: New South Wales
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Toronto
country: Canada
facility: Sunnybrook Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: University of Toronto Hospital
state: Ontario
Study officials:
affiliation: University Health Network, Toronto, Canada
name: Michael Fehlings, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Washington
name: Branko Kopjar, MD, PhD
role: STUDY_DIRECTOR
References:
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.
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. No abstract available.
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. No abstract available.
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.
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.
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.
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.
citation: 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.AOSPINE12112.
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.
citation: Satkunendrarajah K, Nassiri F, Karadimas SK, Lip A, Yao G, Fehlings MG. Riluzole promotes motor and respiratory recovery associated with enhanced neuronal survival and function following high cervical spinal hemisection. Exp Neurol. 2016 Feb;276:59-71. doi: 10.1016/j.expneurol.2015.09.011. Epub 2015 Sep 21.