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SCI JOURNAL CLUB

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David Suarez

on 26 September 2014

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Transcript of SCI JOURNAL CLUB

Limitations
SCI Journal Club
David Suarez, MD

September 25, 2014
Background
After SCI, aim of therapies:
Limit damage to spinal cord
Enhance repair

Accomplished with:
Neuroprotection to limit secondary injury after trauma
Modulating inflammatory response
Modifying glial and fibroblastic scar that blocks regrowth of axons
Stimulating regrowth and repair of damaged axons and provide substrate to guide them

Trauma force and ischemic changes lead to neuronal membrane dysfunction, including activation of voltage-gated sodium channels.

Increase in intracellular sodium

Influx in calcium ions through Na-Ca exchange pump

Increase in extracellular release of toxic levels of excitatory neurotransmitter glutamate

All leads to regional cell death from ionic imbalance, reactive oxidative ions, intracellular energy failure, cytotoxic edema, glutaminergic excitotoxicity.

Riluzole



Sodium-channel blocker
FDA approved for treatment of ALS

Originally developed in 1980s as an anticonvulsant,
Never gained significant footing in treatment of epileptic patients
Has been applied to disease states with aberrant sodium metabolism or glutaminergic excitotoxicity

A) Enhances uptake of ambient glutamate by astrocytes, reduces endogenous release of glutamate
B) Limits level of extracellular glutamate binding to ionotropic receptors that raise intracellular calcium
C) Inhibits persistent sodium current, limiting neuronal excitability, glutamate release, neuronal damage
In ALS:

Impaired synaptic reuptake of glutamate

Contributing to the rapid degeneration of motor neurons

1994 - first phase III placebo-controlled randomized: modest but significant survival benefit with oral riluzole

Cochrane review: >1000 patients with ALS, treated with riluzole (100 mg/day) experienced increase in median tracheostomy-free survival of 2.8 months (15.5 months vs. 13.2 months)

Subtle beneficial effects with respect to limb and bulbar function

Generally safe and well tolerated, but potentially serious risk of serum alanine aminotransferase elevation (at least a 3-fold elevation) - was uniformly reversible with cessation of drug administration

Metabolized in the liver by an enzyme of the CYP 450 family

Half-life is 12 hours, reaches steadystate plasma concentrations in 4–5 half-lives

Also investigated in Huntington dz, Parkinson plus d/o, depression, spinal muscle atrophy type 1, and SCI

Methods
1. Test the feasibility of a trial of a therapy that must be administered
within 12 h of acute traumatic SCI.
2. Study the PK and pharmacodynamics of riluzole in SCI.
3. Obtain data on the safety of riluzole in SCI using a matched
cohort group for comparison.
4. Obtain exploratory pilot data on the effects of riluzole on
measures of neurological outcome after SCI using a matched
cohort group for comparison.
5. Relate the pharmacology of riluzole in SCI to safety and
outcome measures.
Goals
Design:
Phase I, prospective, multi-site, single arm, matched-comparison group, open-label study.
Thomas Jefferson, U. Maryland, U. Virginia, U. Texas, U. Louisville, U. Toronto

Population:

36 participants who received riluzole, and standard of care for SCI
36 matched patients from the North American Clinical Trials Network Spinal Cord Injury Registry who received standard of care

Intervention:
Riluzole 50 mg PO (or NGT) q12h, within 12 hr of injury, for 28 doses.

Dosing:
Human data: ALS best benefit-risk
Animal data: Human equivalent dose scaled from the animal dose in rats

Time of first dose:
based on preclinical trials in rats – locomotor improvement up to 3hrs after injury (changes occur 4-6x more rapidly in rodents)

Outcome measures:
safety, pharmacokinetics, and pilot data on neurological improvement

Results
Feasibility:
Achieved enrollment of 36 pts, AIS A-C, C4-T11, who received riluzole w/i 12h of injury
Mean time to first dose was 8.7 hrs
Injury to admission was 3.0 hrs
35 pts completed study
71% had all 28 doses
26% received 27 doses
3% received 26 doses
There were no statistically significant differences in demographics or clinical variables for the riluzole and registry pt groups

C- and T-spine distribution, impairment scale were matched

Neurological level of injury and impairment grades on admission were similar for riluzole and registry patient groups
Pharmacokinetics:

Plasma concentrations and systemic exposure varied significantly among pts (24-409 ng/mL)

Concentrations were higher on day 3 than 14, resulting from lower clearance and volume of distribution

Complications by system - riluzole group
Safety:
No difference in incidence of complications between groups
No serious adverse effects attributable to riluzole
no deaths

Liver enzyme elevations
9-37% - 1 enzyme elevated on admission
14-70% - 1 enzyme elevated while receiving riluzole
1 severe elevation of AST, 1 of ALT, (corrected by 3 and 6 mo), 1 of GGT
Elevation of 1 enzyme not linked to elevation in others
No relationship between max concentration of riluzole and liver enzyme levels
Neurological Outcomes
Assessed with:
Motor, sensory score progression
Impairment grade conversion
Spinal Cord Independence Measure (comprehensive rating scale that measures the ability of patients to perform everyday tasks according to their value for the patient)

Progression of total motor scores from admission to 42, 90, 180 days
Greatest gains in motor score occurred in grade B patients. Within grade B pts, gain in bilateral LEMS exceeded that of bilateral UEMS

Motor score mean changes from admission to 90 and 180 days
Riluzole and registry mean difference in score change
Mean difference across all grades was 15.5 motor points (p 0.021) at 90 days
Not as impressive at 180 days

Conversion of impairment grades
Higher percentage of Riluzole cohort patients that converted to more functional grade both at 90 and 180 days


Sensory scores
Pinprick scores 10 points higher in riluzole patients at 90 days and 9 points higher at 180s, but not statistically significant

SCIM
No significant change in SCIM scores between the cohorts

Thoracic levels
No significant changes in patients with thoracic injury

Conclusion
Feasibility:
It is possible to screen, enroll, obtain data, and begin therapy within 12 hrs of injury
Pharmacology:
- No significant correlation was found between blood-plasma levels and motor outcome scores.
- Large difference in max concentrations likely due in part to differences in gut absorption and BMI.
- Change in clearance and distribution between days 3 and 14 likely due to the changing physiology of the SCI patient
Safety:
Incidence and types of complications similar between riluzole and registry patients. There were no SAE and no deaths.
Elevated liver enzymes:
- Riluzole associated with mild to mod liver enzyme elevations that appear to be transient.
- At baseline, enzyme elevation has been reported in SCI pts, possibly from decreased blood flow to the liver
Neurological outcomes:
- Not powered to detect significant changes, but trend was present.
- Comparable findings as minocycline trial in improved motor scores and LEMS>UEMS.
- Robust conversions by grade B patients to more functional grade - 87% at 90 d, 100% at 180 d, compared to 60% registry, 67% entire database. But, only 8 pts, and assessed within 12 hr of injury.
Open label
No true control group
Short injury to treatment time
Small N
Lost 26% of pts at 180 d
Clinical Significance
Prospect of another possible agent to decrease neuronal injury and improve recovery
An agent that is already relatively well tolerated
Unfortunately, nothing we would use immediately
Warrants further investigation, which will be pursued
References:

Grossman R, Fehlings M, et al. 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 Neurotraum 31:239-255, 2014.

Wilson J, Fehlings M, et al. Riluzole for Acute Traumatic Spinal Cord Injury: A Promising Neuroprotective Treatment Strategy. World Neurosurg (2014) 81, 5/6:825-829.

Cifra A, Mazzone G, Nistri A. Riluzole: What it Does to Spinal And Brainstem Neurons and How It Does It. 19(2) 137-144, 2012.

Fehlings M, Wilson J, et al. Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial. J Neurosurg Spine (Suppl) 17:151-156, 2012.
Thank You!

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