Neuroprotection With Phenytoin in Optic Neuritis

Multiple Sclerosis Clinical Trial

Official title:

A Phase II Double Blind, Randomized, Placebo Controlled Trial of Neuroprotection With Phenytoin in Acute Optic Neuritis

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01451593
• Other study ID #: UCL/11/0083
• Status: Completed
• Phase: Phase 2
• First received: October 11, 2011
• Last updated: September 8, 2015
• Start date: November 2011
• Est. completion date: March 2015

Study information

• Verified date: September 2015
• Source: University College, London
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 92
• Est. completion date: March 2015
• Est. primary completion date: December 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 60 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Multiple Sclerosis
• Neuritis
• Optic Neuritis

Intervention

Drug:
• Phenytoin
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
placebo identical in appearance to active IMP (phenytoin)

Locations

Country	Name	City	State
United Kingdom	National Hospital for Neurology and Neurosurgery	London
United Kingdom	Royal Hallamshire Hospital	Sheffield

Sponsors (3)

Lead Sponsor	Collaborator
University College, London	Multiple Sclerosis Society of Great Britain and Northern Ireland, National Multiple Sclerosis Society

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Mean Retinal nerve fibre layer thickness	The primary comparison will estimate active versus placebo mean retinal nerve fibre layer thickness of the retinal nerve fibre layer after 6 months, adjusted for the corresponding baseline measurement in the unaffected eye.	Measured at entry and after 6 months	No
Secondary	Visual function	logMAR visual acuity, low contrast sensitvity using 1.25% and 2.5% sloan charts and colour vision using Farnsworth-Munsell 100 Hue test.	Measured at entry and 6 months	No
Secondary	Visual evoked potentials	Measurement of latency and amplitude will be performed. Axonal protection with phenytoin may enable axons to survive long enough to undergo remyelination. VEPS will give independent estimates of remyelination in the optic nerve.	Measured at entry (or within 4 weeks) and after 6 months	No
Secondary	Optic nerve and brain MRI	Brain MRI to detect demyelinating lesions that can be used in considering the prognosis for or diagnosis of multiple sclerosis using McDonald criteria.; Optic nerve MRI - The following sequences will be performed: Fat sat T2 coronal-oblique to visualize the symptomatic lesion and obtain optic nerve area measurements.; 3D gradient echo magnetization transfer sequence MTR to obtain measures of optic nerve myelination.; Diffusion tensor imaging to obtain axial and radial diffusivity metrics of the optic nerve to determine axonal integrity.	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	No