Optic NeuritisPhase 2NCT01451593
Neuroprotection With Phenytoin in Optic Neuritis
A Phase 2 study testing Phenytoin in people with Optic Neuritis and Multiple Sclerosis, run by University College, London at 2 sites in United Kingdom.
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. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Optic Neuritis, Multiple Sclerosis
- What is being tested?
- Phenytoin
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 92 participants
- Where
- 2 sitesUnited Kingdom
- Study dates
- Nov 2011to Mar 2015
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 10Show fewer
- Relapsing remitting MS of greater than 10 yrs duration or EDSS>3
- Pregnancy
- Breast Feeding
- Significant cardiac, renal or liver abnormalities
Trial locations and contacts
2 sites in 1 country.
United Kingdom2 sites
National Hospital for Neurology and Neurosurgery
London, WC1 3BG
Royal Hallamshire Hospital
Sheffield
About this study
Official title: 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.
Read the 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.
- Conditions
- Optic Neuritis, Multiple Sclerosis
- Being tested
- Phenytoin, Placebo
- Keywords
- Optic neuritis, Multiple sclerosis, Retinal nerve fibre layer, Axonal loss, Neuroprotection, Phenytoin, MRI, Optical coherence tomography, Sodium Channel Blockers
- Medical subject headings
- Optic Neuritis, Multiple Sclerosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
PhenytoinDrug
Also called Phenytoin sodium, Epanutin (Flynn Pharma)
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.
PlaceboDrug
placebo identical in appearance to active IMP (phenytoin)
| Study group | Role | What they receive |
|---|---|---|
| phenytoin | Experimental | active arm of trial 1:1 allocation active versus placebo Receives: Drug: Phenytoin |
| placebo | Placebo comparator | 1:1 allocation active versus placebo Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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: Measured at entry and after 6 months
Secondary outcomes (3)
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: Measured at entry and 6 months
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: Measured at entry (or within 4 weeks) and after 6 months
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.
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Oct 2011 (estimated)
- Study startNov 2011
- Primary completionDec 2014
- Study completionMar 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Optic NeuritisStudies of the same condition, open and under way.
- More trials run by University College, LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind
- Who is masked
- Participant, Investigator, Outcomes assessor
- Enrolment
- 92 participants (actual)
Sponsor and investigators
- Lead sponsor
- University College, London
- Sponsor type
- University, hospital or other
- Collaborators
- National Multiple Sclerosis Society, Multiple Sclerosis Society of Great Britain and Northern Ireland
- Responsible party
- Sponsor
- Investigators
- Raju Kapoor, DM FRCP, Principal investigator, Institute of Neurology, University College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01451593
- Sponsor's protocol ID
- UCL/11/0083
- Status last verified
- Sep 2015
- First submitted
- 11 Oct 2011
- Last updated
- 9 Sep 2015
- Results posted
- No
- Data monitoring committee
- Yes
Publications
Kodali S, Bianchi A, Raftopoulos R, Moccia M, Malladi AP, Yiannakas MC, Fugger M, Samson RS, Wheeler-Kingshott CAM, Koltzenburg M, Prados F, Hickman S, Kapoor R, Toosy AT. Effects of Phenytoin on the Retinal Ganglion Cell-Inner Plexiform Layer in Acute Optic Neuritis: Analysis of a Phase II Randomized Trial. Neurology. 2025 Oct 21;105(8):e213951. doi: 10.1212/WNL.0000000000213951. Epub 2025 Sep 25.
PubMed 40997284Raftopoulos 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.
PubMed 26822749Counihan 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.
PubMed 24287594
Study at a glance
From the registry record, last updated by the sponsor on 9 Sep 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Double Blind, Randomized, Placebo Controlled Trial of Neuroprotection With Phenytoin in Acute Optic Neuritis
- ClinicalTrials.gov ID
- NCT01451593
- Acronym / sponsor ID
- UCL/11/0083
- Conditions
- Optic Neuritis, Multiple Sclerosis
- Keywords
- Optic neuritis, Multiple sclerosis, Retinal nerve fibre layer, Axonal loss, Neuroprotection, Phenytoin, MRI, Optical coherence tomography
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 92 participants (actual)
- Lead sponsor
- University College, LondonUniversity, hospital or other
- Collaborators
- National Multiple Sclerosis Society, Multiple Sclerosis Society of Great Britain and Northern Ireland
- Study start
- Nov 2011
- Primary completion
- Dec 2014 (actual)
- Study completion
- Mar 2015 (actual)
- First posted
- 13 Oct 2011 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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 design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Triple blind (participant, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| phenytoin | Experimental | Drug: Phenytoinactive arm of trial 1:1 allocation active versus placebo |
| placebo | Placebo comparator | Drug: Placebo1:1 allocation active versus placebo |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (5 listed)
- 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
Key exclusion criteria (10 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| PhenytoinAlso: Phenytoin sodium, Epanutin (Flynn Pharma)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. | Drug | phenytoin |
| Placeboplacebo identical in appearance to active IMP (phenytoin) | Drug | placebo |
Primary outcome
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.
3 secondary outcomes
Visual function
Time frame: Measured at entry and 6 months
Visual evoked potentials
Time frame: Measured at entry (or within 4 weeks) and after 6 months
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 9 Sep 2015.
- Derived from this study: PubMed 40997284Kodali S, Bianchi A, Raftopoulos R, Moccia M, Malladi AP, Yiannakas MC, Fugger M, Samson RS, Wheeler-Kingshott CAM, Koltzenburg M, Prados F, Hickman S, Kapoor R, Toosy AT. Effects of Phenytoin on the Retinal Ganglion Cell-Inner Plexiform Layer in Acute Optic Neuritis: Analysis of a Phase II Randomized Trial. Neurology. 2025 Oct 21;105(8):e213951. doi: 10.1212/WNL.0000000000213951. Epub 2025 Sep 25.
- Derived from this study: PubMed 26822749Raftopoulos 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.
- Derived from this study: PubMed 24287594Counihan 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Raju Kapoor, DM FRCP principal investigator
Institute of Neurology, University College London
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Phenytoin in people with Optic Neuritis and Multiple Sclerosis, run by University College, London at 2 sites in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 9 Sep 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean Retinal nerve fibre layer thickness (time frame: Measured at entry and after 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01451593, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 9 Sep 2015.