Neuroprotection With Phenytoin in Optic Neuritis
Condition: Optic Neuritis; Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Neuritis; Optic Neuritis; Sclerosis
Study type: Interventional
Phase: Phase 2

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.
    

Intervention name(s): Phenytoin; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Phenytoin will be loaded using at total dose of 15mg/kg (rounded to the nearest 100mg) divided into three equal doses given once daily for 3 days.This will be followed by a daily maintenance dose of 4mg/kg once a day (rounded up to the nearest 50mg, with a maximum dose of 300mg)for 13 weeks.Phenytoin levels will be taken at 1 and 3 months.; placebo identical in appearance to active IMP (phenytoin)
Other intervention name(s): Phenytoin sodium; Epanutin (Flynn Pharma)
Intervention MeSH terms: Phenytoin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Optic neuritis; Multiple sclerosis; Retinal nerve fibre layer; Axonal loss; Neuroprotection; Phenytoin; MRI; Optical coherence tomography; Sodium Channel Blockers