A phase II double-blind, randomised, placebo-controlled trial of neuroprotection with phenytoin in acute optic neuritis

INTERVENTION: Trade Name: Phenytoin Sodium Flynn Hard Capsules 25 mg, 50 mg, 100 mg hard capsules Product Name: Phenytoin Sodium Pharmaceutical Form: Capsule INN or Proposed INN: 5,5‐diphenylimidazolidine‐2,4‐dione monosodium salt CAS Number: 630‐93‐3 Other descriptive name: phenytoin sodium; Sodium 5,5‐DIPHENYLHYDANTOIN; Diphenylhydantoin monosodium salt Concentration unit: mg milligram(s) Concentration type: range Concentration number: 25‐100 Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use CONDITION: Acute demyelinating optic neuritis ; MedDRA version: 16.0 Level: PT Classification code 10030942 Term: Optic neuritis System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] SECONDARY OUTCOME: Secondary end point(s): 1. Does phenytoin improve visual outcome? This represents a secondary endpoint in the present study, since the inbuilt redundancy of the nervous system suggests that it will be more difficult to demonstrate an effect of treatment on visual function than on atrophy. For this first clinical study atrophy has therefore been chosen as a more sensitive surrogate marker to be the primary endpoint, but detailed measurements of visual function will also be undertaken.; 2. Does phenytoin promote remyelination of the optic nerve? As discussed above, axonal protection by phenytoin may enable axons to survive long enough to undergo remyelination, which may further promote their long term integrity. MRI techniques and measurements of the visual evoked potential will be made to give independent estimates of axonal loss and remyelination in the optic nerve.; 3. Biomarkers a) DNA will be collected for pharmacogenomics studies and for analysis of potential genetic polymorphisms associated with poor outcome; b) plasma neurofilament heavy chain (NfH) levels; 4. Is treatment with phenytoin associated with unexpected adverse effects? While treatment is expected to provide neuroprotection in this setting, we will evaluate participants for any unanticipated adverse effects that occur instead, using the results of the primary and secondary endpoints, and the occurrence of adverse clinical events. Timepoint(s) of evaluation of this end point: 1. Visual outcome: baseline, 6 months; 2. Remyelination: baseline, 6 months; 3. Biomarkers: baseline, 1, 2, 3, 6 months; 4. Unexpected adverse events: baseline, 1, 2, 3, 6 months PRIMARY OUTCOME: Main Objective: In optic neuritis, there is inflammation of the optic nerve, which carries visual information from the eye into the brain. People with optic neuritis lose vision in the eye affected by the disorder, and vision may not recover fully. ; Current therapy for optic neuritis can lead to a faster recovery of vision, but does not improve the extent to which vision would recover eventually without treatment. Recent work suggests that loss of vision is due to damage to the nerve fibres in the optic nerve (which is accompanied by damage to the nerve fibres in the retina), that the damage is secondary to a buildup of sodium in these fibres, and that it can be prevented by blocking the entry of sodium into them. ; In this clinical trial, the principal objective is to assess whether immediate and sustained blockade of the entry of sodium into nerve fibres with the drug phenytoin protects nerve fibres in the retina and optic nerve from degeneration after an attack of optic neuritis. ; Primary end point(s): The primary outcome measure is the thickness of the retinal nerve fibre layer (RNFL). The sample size of 45 participants per arm provides a power of 80% to detect a treatment effect of 50% at 5% significance level (two‐tailed), comparing mean follow‐up affected eye RNFL adjusted for baseline unaffected eye RNFL (a conventional ANCOVA adjusting for baseline affected eye RNFL is avoided because of affected eye inflammation at baseline). For this calculation, 100% treatment effect was taken as the mean difference between six‐month unreated affected eye RNFL and baseline unaffected eye RNFL,using longitudinal data from our previous natural history study of optic neuritis. Secondary Objective: The secondary objectives of the research are to assess whether treatment with phenytoin also improves the extent to which vision itself recovers after optic neuritis, whether phenytoin promotes repair of the optic nerve, to assess its effects on chemical markers of nerve fibre injury in the blood and urine that could be used to measure beneficial effects of therapy more easily in future trials, and finally to evaluate the safety of treatment with phenytoin in this setting.; Timepoint(s) of evaluation of this end point: At baseline and at 6 months INCLUSION CRITERIA: a) A clinical diagnosis of acute unilateral optic neuritis (with or without a prior diagnosis of MS), with a visual acuity of = 6/9 (20/30) and an interval between onset of visual loss and randomization of = 14 days. b) Age 18‐60 years. The lower limit has been chosen so informed consent can be obtained, and the upper limit to avoid including participants with cerebrovascular disease, which would potentially influence the cerebral MRI appearances. c) Gender. Men and women will be included, but we will perform an initial pregnancy test for women of childbearing age, who will be required to use appropriate methods of contraception during treatment with phenytoin and for 6 weeks afterwards to avoid any teratogenic effects of phenytoin. d) Patients with a prior diagnosis of relapsing MS (whether or not being treated with Glatiramer Acetate or beta‐Interferon) are eligible, if =10yr history of MS, and Extended Disability Status Score (EDSS) =3. e) Con