- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01451593
Neuroprotection With Phenytoin in Optic Neuritis
A Phase II Double Blind, Randomized, Placebo Controlled Trial of Neuroprotection With Phenytoin in Acute Optic Neuritis
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.
Study Overview
Status
Conditions
Intervention / Treatment
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
Enrollment (Actual)
Phase
- Phase 2
Contacts and Locations
Study Locations
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London, United Kingdom, WC1 3BG
- National Hospital For Neurology and Neurosurgery
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Sheffield, United Kingdom
- Royal Hallamshire Hospital
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
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 Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: phenytoin
active arm of trial 1:1 allocation active versus placebo
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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:
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Placebo Comparator: placebo
1:1 allocation active versus placebo
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placebo identical in appearance to active IMP (phenytoin)
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Mean Retinal nerve fibre layer thickness
Time Frame: Measured at entry and after 6 months
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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.
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Measured at entry and after 6 months
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Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Visual function
Time Frame: Measured at entry and 6 months
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logMAR visual acuity, low contrast sensitvity using 1.25% and 2.5% sloan charts and colour vision using Farnsworth-Munsell 100 Hue test.
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Measured at entry and 6 months
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Visual evoked potentials
Time Frame: Measured at entry (or within 4 weeks) and after 6 months
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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.
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Measured at entry (or within 4 weeks) and after 6 months
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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
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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:
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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
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Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Raju Kapoor, DM FRCP, Institute of Neurology, University College London
Publications and helpful links
General Publications
- 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.
- 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.
Study record dates
Study Major Dates
Study Start
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Pathologic Processes
- Nervous System Diseases
- Immune System Diseases
- Demyelinating Autoimmune Diseases, CNS
- Autoimmune Diseases of the Nervous System
- Demyelinating Diseases
- Autoimmune Diseases
- Eye Diseases
- Neuromuscular Diseases
- Peripheral Nervous System Diseases
- Optic Nerve Diseases
- Cranial Nerve Diseases
- Multiple Sclerosis
- Sclerosis
- Neuritis
- Optic Neuritis
- Molecular Mechanisms of Pharmacological Action
- Membrane Transport Modulators
- Anticonvulsants
- Voltage-Gated Sodium Channel Blockers
- Sodium Channel Blockers
- Cytochrome P-450 CYP1A2 Inducers
- Cytochrome P-450 Enzyme Inducers
- Phenytoin
Other Study ID Numbers
- UCL/11/0083
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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