Riluzole in Spinal Cord Injury Study

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.

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