RISCIS: Riluzole in Spinal Cord Injury Study

Sponsor

AOSpine North America Research Network (Other)

Overall Status

Terminated

CT.gov ID

NCT01597518

Collaborator

AO Foundation, AO Spine (Other), United States Department of Defense (U.S. Fed), Rick Hansen Institute (Other), Christopher Reeve Paralysis Foundation (Other)

193

Enrollment

Locations

Arms

84.2

Actual Duration (Months)

6.7

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Spinal Cord Injury	Drug: Riluzole Drug: Placebo	Phase 2/Phase 3

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 Design

Study Type:

Interventional

Actual Enrollment :

193 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Oct 1, 2013

Actual Primary Completion Date :

Oct 8, 2020

Actual Study Completion Date :

Oct 8, 2020

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Riluzole

Drug: Riluzole

100mg BID first 24 hours after the injury; 50mg BID 2--14 days following the injury

Placebo Comparator: Placebo

Drug: Placebo

Placebo 2x in first 24 hours; Placebo 2x day 2--14

Outcome Measures

Primary Outcome Measures

Change in ISNCSCI Total Motor Score between 180 days and baseline [180 Days]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

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

Sponsors and Collaborators

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

Investigators

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