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    Summary
    EudraCT Number:2011-003475-11
    Sponsor's Protocol Code Number:UCL/11/0083
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2011-08-24
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2011-003475-11
    A.3Full title of the trial
    A phase II double-blind, randomised, placebo-controlled trial of neuroprotection with phenytoin in acute optic neuritis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Neuroprotection with phenytoin in optic neuritis
    A.3.2Name or abbreviated title of the trial where available
    Neuroprotection with phenytoin in optic neuritis
    A.4.1Sponsor's protocol code numberUCL/11/0083
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College London (UCL)
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportNational Multiple Sclerosis Society
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportMultiple Sclerosis Society
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity College London (UCL)
    B.5.2Functional name of contact pointEvans
    B.5.3 Address:
    B.5.3.1Street AddressJoint Research Office, UCL, Gower Street,
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeWC1E 6BT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number020 7679 6802
    B.5.5Fax number020 3108 2312
    B.5.6E-maila.j.evans@ucl.ac.uk
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Phenytoin Sodium Flynn Hard Capsules 25 mg, 50 mg, 100 mg hard capsules
    D.2.1.1.2Name of the Marketing Authorisation holderFlynn Pharma Ltd
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePhenytoin Sodium
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INN5,5-diphenylimidazolidine-2,4-dione monosodium salt
    D.3.9.1CAS number 630-93-3
    D.3.9.3Other descriptive namephenytoin sodium; Sodium 5,5-DIPHENYLHYDANTOIN; Diphenylhydantoin monosodium salt
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number25 to 100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute demyelinating optic neuritis
    E.1.1.1Medical condition in easily understood language
    Inflammation of the optic nerve, which carries visual signals from the eye to the brain, leading to loss of vision.
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    E.1.2Level PT
    E.1.2Classification code 10030942
    E.1.2Term Optic neuritis
    E.1.2System Organ Class 10029205 - Nervous system disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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.
    E.2.2Secondary objectives of the trial
    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.
    E.2.3Trial contains a sub-study No
    E.3Principal 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) Considered able to comply with all study requirements.
    E.4Principal exclusion criteria
    a) Any co-morbid ocular disease or previous history of optic neuritis in either eye, as this would interfere with the assessment of outcome.
    b) Use of Na+ or Ca2+ channel blockers in the previous 2 weeks, corticosteroids in the previous 2 months, or immunosuppressive/immunomodulatory drugs (including natalizumab) in the previous 3 months.
    c) Cardiac, hepatic or renal abnormalities, either in the clinical history or in screening blood tests. Screening ECG will be obtained, and patients with other major systemic diseases will also be excluded.
    d) Past untoward reactions or other contraindications to phenytoin, or disabling temperature-dependent symptoms related to MS.
    e) Contraindications to phenytoin, including concomitant medications.
    f) Standard contraindications to MR imaging.
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At baseline and at 6 months
    E.5.2Secondary 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.
    E.5.2.1Timepoint(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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    The end of the trial will be the date of the last visit by the last participant.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months6
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 90
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state90
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    The intervention is designed to provide neuroprotection only during the acute phase of the condition, so that ongoing treatment when the attack has ended would not be indicated. As this is a phase II trial with a surrogate primary outcome measure, there are also no plans to provide IMP for future demyelinating attacks, pending full analysis of the results.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-10-05
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2011-11-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-12-06
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