Multiple Sclerosis Clinical Trial
Official title:
A Phase II Double Blind, Randomized, Placebo Controlled Trial of Neuroprotection With Phenytoin in Acute Optic Neuritis
Optic neuritis is caused by inflammation of the optic nerve and causes loss of vision in the
affected eye. It is often associated with multiple sclerosis. Loss of vision after an attack
of optic neuritis is caused by damage to the nerve fibres in the optic nerve. There are a
number of factors that contribute to nerve fibre damage including increased levels of sodium
within them, so blocking sodium entry could help to protect them against damage.
The purpose of this study is determine whether phenytoin (which blocks sodium entry into
cells) can protect against loss of nerve fibres and prevent loss of vision after optic
neuritis.
Demyelinating optic neuritis is the most common cause of acute reversible visual loss in
young adults of Northern European Origin. There is a strong association with multiple
sclerosis and up to 75% of British adults with acute clinically isolated optic neuritis go
on to develop MS during long term follow up. Equally, 70% of MS patients have clinical
evidence if optic nerve involvement during the course of their illness.
The pathology of the acute inflammatory lesion is comparable to the plaques found elsewhere
in the CNS in MS. The retina and optic nerve therefore represent a discrete compartment of
the CNS affected by the disease process that can be easily studied using a combination of
clinical, electrophysiological and imaging techniques.
There is good evidence that axonal and neuronal degeneration are the primary pathological
processes leading to irreversible disability in MS. Experimental models have demonstrated
numerous mechanisms of axonal loss including adaptive changes in the demyelinated axonal
membrane, in particular increased density of sodium channels leading to increased
concentrations of intraaxonal sodium ions. Partial blockade of voltage gated sodium channels
with drugs such as phenytoin has been shown to be neuroprotective in several experimental
models of inflammatory axonal injury.
The retinal nerve fibre layer is unique in the CNS in that it is not myelinated and
therefore is an ideal biomarker for the processes of neurodegeneration and neuroprotection.
Imaging of the retinal nerve fibre layer using optical coherence tomography and of the optic
nerve using MRI both demonstrate that acute optic neuritis is associated with significant
volume loss, and this correlates well with impaired visual function.
The primary aim of this trial is to assess whether sodium channel blockade with phenytoin
has a neuroprotective effect on axonal loss after an attack of acute demyelinating optic
neuritis. Secondary aims are to assess whether phenytoin improves visual outcome and
remyelination and to assess the safety of the treatment.
90 patients with acute optic neuritis will be recruited into a double blind placebo
controlled trial in which patients will be randomly allocated to receive either phenytoin or
placebo for 3 months. Recruitment will take place at two trial sites in Sheffield and
London. The trial is powered to detect a 50% beneficial effect on the primary outcome
measure. Outcome will be measured at entry and after 6 months.Bias will be minimized by
blinding assessing physicians and patients using active and placebo treatment of identical
appearance.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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