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Neuroprotection With Phenytoin in Optic Neuritis

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01451593
Recruitment Status : Completed
First Posted : October 13, 2011
Last Update Posted : September 9, 2015
Sponsor:
Collaborators:
National Multiple Sclerosis Society
Multiple Sclerosis Society of Great Britain and Northern Ireland
Information provided by (Responsible Party):
University College, London

Tracking Information
First Submitted Date  ICMJE October 11, 2011
First Posted Date  ICMJE October 13, 2011
Last Update Posted Date September 9, 2015
Study Start Date  ICMJE November 2011
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: December 10, 2014)
Mean Retinal nerve fibre layer thickness [ Time Frame: Measured at entry and after 6 months ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: October 11, 2011)
Mean Retinal nerve fibre layer thickness [ Time Frame: Measured at entry and after 6 months ]
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 inaffected eye.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: December 10, 2014)
  • Visual function [ Time Frame: Measured at entry and 6 months ]
    logMAR visual acuity, low contrast sensitvity using 1.25% and 2.5% sloan charts and colour vision using Farnsworth-Munsell 100 Hue test.
  • Visual evoked potentials [ Time Frame: Measured at entry (or within 4 weeks) and after 6 months ]
    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.
  • Optic nerve and brain MRI [ Time Frame: 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 ]
    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:
    1. Fat sat T2 coronal-oblique to visualize the symptomatic lesion and obtain optic nerve area measurements.
    2. 3D gradient echo magnetization transfer sequence MTR to obtain measures of optic nerve myelination.
    3. Diffusion tensor imaging to obtain axial and radial diffusivity metrics of the optic nerve to determine axonal integrity.
Original Secondary Outcome Measures  ICMJE
 (submitted: October 11, 2011)
  • Visual function [ Time Frame: Measured at entry and 6 months ]
    logMAR visual acuity, low contrast sensitvity using 1.25% and 2.5% sloan charts and colour vision using Farnsworth-Munsell 100 Hue test.
  • Visual evoked potentials [ Time Frame: Measured at entry (or within 4 weeks) and after 6 months ]
    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 independant estimates of remyelination in the optic nerve.
  • Optic nerve and brain MRI [ Time Frame: 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 ]
    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:
    1. Fat sat T2 coronal-oblique to visualize the symptomatic lesion and obtain optic nerve area measurements.
    2. 3D gradient echo magnetization transfer sequence MTR to obtain measures of optic nerve myelination.
    3. Diffusion tensor imaging to obtain axial and radial diffusivity metrics of the optic nerve to determine axonal integrity.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neuroprotection With Phenytoin in Optic Neuritis
Official Title  ICMJE A Phase II Double Blind, Randomized, Placebo Controlled Trial of Neuroprotection With Phenytoin in Acute Optic Neuritis
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Optic Neuritis
  • Multiple Sclerosis
Intervention  ICMJE
  • 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.
    Other Names:
    • Phenytoin sodium
    • Epanutin (Flynn Pharma)
  • Drug: Placebo
    placebo identical in appearance to active IMP (phenytoin)
Study Arms  ICMJE
  • Experimental: phenytoin
    active arm of trial 1:1 allocation active versus placebo
    Intervention: Drug: Phenytoin
  • Placebo Comparator: placebo
    1:1 allocation active versus placebo
    Intervention: Drug: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: September 8, 2015)
92
Original Estimated Enrollment  ICMJE
 (submitted: October 11, 2011)
90
Actual Study Completion Date  ICMJE March 2015
Actual Primary Completion Date December 2014   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 60 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01451593
Other Study ID Numbers  ICMJE UCL/11/0083
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party University College, London
Study Sponsor  ICMJE University College, London
Collaborators  ICMJE
  • National Multiple Sclerosis Society
  • Multiple Sclerosis Society of Great Britain and Northern Ireland
Investigators  ICMJE
Principal Investigator: Raju Kapoor, DM FRCP Institute of Neurology, University College London
PRS Account University College, London
Verification Date September 2015

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP