A double blind randomised controlled trial on neuroprotection of amiloride in optic neuritis

INTERVENTION: Trade Name: Amiloride Product Name: Amiloride Pharmaceutical Form: Capsule INN or Proposed INN: Amiloride Hydrochloride CAS Number: 2016‐88‐8 Concentration unit: mg milligram(s) Concentration type: equal Concentration number: 10‐ Pharmaceutical form of the placebo: Capsule Route of administration of the placebo: Oral use CONDITION: Optic Neuritis ; MedDRA version: 14.1 Level: PT Classification code 10030942 Term: Optic neuritis System Organ Class: 10029205 ‐ Nervous system disorders Therapeutic area: Diseases [C] ‐ Nervous System Diseases [C10] 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 ß‐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 pe PRIMARY OUTCOME: Main Objective: 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 Primary 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 Secondary Objective: 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 Timepoint(s) of evaluation of this end point: Six months SECONDARY OUTCOME: Secondary 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) Timepoint(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