Clinical trial NCT01451593: Neuroprotection With Phenytoin in Optic Neuritis
Official title: A Phase II Double Blind, Randomized, Placebo Controlled Trial of Neuroprotection With Phenytoin in Acute Optic Neuritis
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Optic Neuritis
Multiple Sclerosis
Keywords: Optic neuritis
Multiple sclerosis
Retinal nerve fibre layer
Axonal loss
Neuroprotection
Phenytoin
MRI
Optical coherence tomography
Sodium Channel Blockers
Lead sponsor: University College, London
Sponsor class: OTHER
Collaborators: name: National Multiple Sclerosis Society
name: Multiple Sclerosis Society of Great Britain and Northern Ireland
First posted: 2011-10-13
Enrollment: 92
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: Inclusion Criteria:

* Diagnosis of acute optic neuritis
* Visual acuity in affected eye ≤ 6/12
* Corrected vision in normal eye ≥ 6/6
* No history of optic neuritis or other ocular disease in either eye
* ≤ 14 days since onset of visual loss

Exclusion Criteria:

* Contraindication or known allergy to Phenytoin
* Contraindication to MRI
* Use of a calcium channel or sodium channel blocker in the past 2 months
* Corticosteroid use in the past 2 months
* Tysabri infusion in the past 3 months
* MS with major temperature dependent disability
* Relapsing remitting MS of greater than 10 yrs duration or EDSS\>3
* Pregnancy
* Breast Feeding
* Significant cardiac, renal or liver abnormalities

Primary outcomes:
measure: Mean Retinal nerve fibre layer thickness
timeFrame: Measured at entry and after 6 months
Secondary outcomes:
measure: Visual function
timeFrame: Measured at entry and 6 months
measure: Visual evoked potentials
timeFrame: Measured at entry (or within 4 weeks) and after 6 months
measure: Optic nerve and brain MRI
timeFrame: Brain MRI will be performed at entry(or within 4 weeks) Optic nerve MRI will be performed at entry (or within 4 weeks) and after 6 months
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: National Hospital for Neurology and Neurosurgery
city: Sheffield
country: United Kingdom
facility: Royal Hallamshire Hospital
Study officials:
affiliation: Institute of Neurology, University College London
name: Raju Kapoor, DM FRCP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Raftopoulos R, Hickman SJ, Toosy A, Sharrack B, Mallik S, Paling D, Altmann DR, Yiannakas MC, Malladi P, Sheridan R, Sarrigiannis PG, Hoggard N, Koltzenburg M, Gandini Wheeler-Kingshott CA, Schmierer K, Giovannoni G, Miller DH, Kapoor R. Phenytoin for neuroprotection in patients with acute optic neuritis: a randomised, placebo-controlled, phase 2 trial. Lancet Neurol. 2016 Mar;15(3):259-69. doi: 10.1016/S1474-4422(16)00004-1. Epub 2016 Jan 26.
citation: Counihan TJ, Duignan JA, Gormley G, Saidha S, Dooley C, Newell J. Does long-term partial sodium channel blockade alter disease progression in MS? Evidence from a retrospective study. Ir J Med Sci. 2014 Mar;183(1):117-21. doi: 10.1007/s11845-013-1042-7. Epub 2013 Nov 28.