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    Summary
    EudraCT Number:2012-004980-39
    Sponsor's Protocol Code Number:Amiloride02
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:GB - no longer in EU/EEA
    Date on which this record was first entered in the EudraCT database:2013-01-22
    Trial 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 number2012-004980-39
    A.3Full title of the trial
    A double blind randomised controlled trial on neuroprotection of amiloride in optic neuritis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    The Amiloride Clinical Trial in Optic Neuritis - does amiloride protect nerve cells from injury after an episode of optic nerve inflammation?
    A.3.2Name or abbreviated title of the trial where available
    Amiloride Clinical Trial in Optic Neuritis Version 1.0
    A.4.1Sponsor's protocol code numberAmiloride02
    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 of Oxford
    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 supportMultiple Sclerosis Society of Great Britain and Northern Ireland
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 Amiloride
    D.2.1.1.2Name of the Marketing Authorisation holderActavis UK 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 nameAmiloride
    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 INNAmiloride Hydrochloride
    D.3.9.1CAS number 2016-88-8
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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
    Optic Neuritis
    E.1.1.1Medical condition in easily understood language
    Inflammation of the nerve supplying the eye, one of the common first events in Multiple Sclerosis, a condition in which there is inflammation in multiple parts of the nervous system
    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 14.1
    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
    To assess amiloride, a commonly used water tablet, as a drug that may protect from loss of nerve cells after an episode of Optic Neuritis (ON). ON is an inflammation of the optic nerve (the nerve that carries signals from the eye) and is a common event in Multiple Sclerosis (MS). MS is a disease in which there are episodes of inflammation in either or all of the brain, the spinal cord and the optic nerves (optic neuritis). These episodes generally recover, however following an episode some of the nerve cells are lost. Loss of nerve cells is an important underlying reason for patients with MS to develop disability. In ON this loss of nerve cells can be easily visualised by non-invasive scanning techniques (Optical coherence tomography [OCT] and Scanning laser polarimetry[GDx]) that measure the thickness of the nervous tissue at the back of the eye, known as the retinal nerve fibre layer (RNFL). We know that after an episode of ON, because some nerve cells are lost, this layer th
    E.2.2Secondary objectives of the trial
    To assess markers of neurodegeneration in ON and the potential neuroprotective effect of amiloride through non-conventional MRI outcomes MRI scans are used routinely in patients with MS and ON. However, although conventional MRI scans can give some useful diagnostic information, more sophisticated techniques are evolving to demonstrate whether nerve cells are surviving or not. Following a group of patients with ON in a clinical trial such as this is an opportunity to apply these non-invasive techniques that have been developed and used in cross sectional studies or in smaller groups in the past. By using these MRI techniques in our groups, we would not only help to assess any protective effect of amiloride, but also help evaluate which of these methods is most useful in clinical trials on MS in the future. To assess whether treatment with amiloride improves functional and visual outcomes following ON Most patients are left with some degree of visual impairment in the affected
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Patients with a first episode of unilateral ON • Participants with an existing diagnosis of relapsing remitting MS and new onset of ON are eligible if they have; Not had a previous episode of ON, A duration of disease of ≤ 10 years An EDSS (Expanded Disability Status Scale) of ≤3. No immune modulating treatment other than β-Interferon or Glatiramer Acetate at time of recruitment • Able to be randomised within 28 days of onset of visual symptoms • Visual acuity of ≤6/9 • Participant is willing and able to give informed consent for participation in the study and able to comply with study visits • Male or Female, aged between18 – 55 years. • Stable dose of current regular medication for at least 4 weeks prior to study entry. • Female participants of child bearing potential must be willing to use two effective methods of contraception (barrier methods, hormonal methods or abstinence) during the initial 5 month treatment period of the study and for one month thereafter. • Participant has clinically acceptable urea and electrolytes and estimated glomerular filtration rate (eGFR) >60 • Able and willing to comply with all study requirements. • Willing to allow his or her General Practitioner to be notified of participation in the study.
    E.4Principal exclusion criteria
    • Previous diagnosis of ON • Any concomitant immune suppressing or immune modulating therapy excluding β-interferon or glatiramer acetate. • Female participants who are pregnant, lactating or planning pregnancy during the course of the study. • Concomitant potassium supplements, angiotensin converting enzyme inhibitors, angiotensin II antagonists, cyclosporine, tacrolimus or lithium • Any contra-indication to MRI – severe claustrophobia, metal implant, pacemaker, etc. • Participant who is terminally ill or is inappropriate for placebo medication • Impaired renal function : eGFR ≤60, anuria, acute or chronic renal insufficiency and evidence of diabetic nephropathy • Raised serum potassium (K+ >5.5mmol/l) • Diabetes • Significant concomitant eye disease in either eye that may affect diseased or fellow eye results. • Any other significant disease or disorder which, in the opinion of the investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant’s ability to participate in the study. • Participants who have participated in another research study involving an investigational product in the past 12 weeks.
    E.5 End points
    E.5.1Primary end point(s)
    Scanning laser polarimetry (GDx) determined difference in retinal nerve fibre layer (RNFL) thickness at 6 months between affected eye and non-affected fellow eye at baseline between the amiloride and placebo group
    E.5.1.1Timepoint(s) of evaluation of this end point
    Six months
    E.5.2Secondary end point(s)
    a) Optical Coherence Tomography (OCT) determined difference in RNFL thickness at 6 months and 12 between affected eye and non-affected fellow eye at baseline between the amiloride and placebo group b) GDX difference in RNFL thickness at 126 months between affected eye and non-affected fellow eye at baseline between the amiloride and placebo group c) Differences between the amiloride and placebo groups in non-conventional magnetic resonance imaging (MRI) surrogate markers of white matter and grey matter injury by 3T scanning at baseline, 6 and 12 months; • Diffusion weighted imaging (DWI) – measure fractional anisotropy(FA), mean diffusivity (MD), axial and radial diffusivity (RD) of the posterior visual tracts • High Resolution T1-weighted image measure of grey matter density and thickness volume • Magnetic Resonance Spectroscopy (MRS) measures of N-acetylaspartate (NAA) in the visual cortex • Resting state network patterns of activity • Magnetisation transfer imaging measures of magnetisation transfer of the white and grey matter d) Differences between the amiloride and placebo groups in visual outcome measures; • High and low contrast visual acuity at baseline, 6 and 12 months • Humphrey 30-2 visual fields (HVF) at baseline, 6 and 12 months • Farnsworth Munsell 100-Hue colour vision test (FM100) at baseline and 6 months e) Differences between the amiloride and placebo groups in electrophysiological changes from baseline and 6 months; • Pattern Visually evoked potential (PVEP)- Mean change in latency and amplitude of PVEP • Pattern Electroretinogram (PERG) – Mean change in amplitute f) Differences between the amiloride and placebo groups in visual quality of life measures at 6 and 12 months; • 25 Item national eye institutes visual function questionnaire (NEI-VFQ-25) • 10 Item neuro ophthalmic supplement (10-NOS)
    E.5.2.1Timepoint(s) of evaluation of this end point
    a/ Baseline, 6 & 12 months b/ Baseline & 12 months (and 6 months for primary end point) c/ Baseline, 6 & 12 months d/ Baseline, 6 & 12 months, (except for FM100, baseline & 6 months only) e/ Baseline & 6 months f/ Baseline, 6 & 12 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 No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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
    LVLS
    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 months0
    E.8.9.1In the Member State concerned days5
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 46
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state46
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 46
    F.4.2.2In the whole clinical trial 46
    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)
    Patients will return to their routine care once the research has finished. Most patients with an uncomplicated optic neuritis will have been discharged from specialist care within the 12 month period from ongoing clinical follow up. The trial drug will have been stopped in the early half of the trial. The results of the study will be published in a peer-reviewed journal, but as this is a phase II study, amiloride will require
    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 Decision2013-01-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-01-21
    P. End of Trial
    P.End of Trial StatusGB - no longer in EU/EEA
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