Tuesday, 21 May 2013

Phenytoin in Acute Optic Neuritis: trial recruitment update

"Our phenytoin in acute optic neuritis trial sponsored by the National MS Society has been running since Feb 2012. Despite cynics stating that we would not recruit very quickly things are going very well; we have now randomised 51 Optic Neurite-ers (ONers) to the study. We are confident that we will reach our target of 90 ONers before the end of the year."





"The main objective of this study is to see if we can protect nerves in acutely inflamed lesions from being transected and dying. If we are able to protect them hopefully they will be remyelinated and survive. If this trial is positive  then this strategy could be extended to MS in general. This study concept was developed in Mouse Doctors optic neuritis model as part or PROMISE 2010."

Neuroprotection With Phenytoin in Optic Neuritis

ClinicalTrials.gov identifier: NCT01451593


Detailed Description of Trial:

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
  1. Ages Eligible for Study: 18 Years to 60 Years
  2. Genders Eligible for Study: Both
  3. Accepts Healthy Volunteers: No
Criteria
Inclusion Criteria
:

  1. Diagnosis of acute optic neuritis
  2. Visual acuity in affected eye ≤ 6/12
  3. Corrected vision in normal eye ≥ 6/6
  4. No history of optic neuritis or other ocular disease in either eye
  5. ≤ 14 days since onset of visual loss
Exclusion Criteria:
  1. Contraindication or known allergy to Phenytoin
  2. Contraindication to MRI
  3. Use of a calcium channel or sodium channel blocker in the past 2 months
  4. Corticosteroid use in the past 2 months
  5. Tysabri infusion in the past 3 months
  6. MS with major temperature dependent disability
  7. Relapsing remitting MS of greater than 10 yrs duration or EDSS>3
  8. Pregnancy
  9. Breast Feeding
  10. Significant cardiac, renal or liver abnormalities
Contacts: Dr Rhian E Raftopoulos - r.raftopoulos@ucl.ac.uk

3 comments:

  1. Dalfampridine has shown promise in improving vision. Are blocking K and Na channels related in neuroprotection?

    ReplyDelete
    Replies
    1. Blocking sodium channels may be neuroprotective. Blocking potassium channels will potentially do the opposite. This has always been my concern with fampridine.

      Delete
  2. It sounds promising, how confident are you that it will have a positive result?

    ReplyDelete

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