Amiloride Clinical Trial In Optic Neuritis (ACTION)
Optic neuritis (ON) is a common event in Multiple Sclerosis (MS), and causes significant loss of nerve cells in the eye, resulting in poor vision. Optic neuritis also provides a sensitive way of testing the effectiveness of drugs that may help protect from loss of nerve cells in ON and therefore in MS.
The investigators have identified through laboratory and early clinical research in humans that amiloride (a water tablet already in use) may be a drug that can be of benefit in optic neuritis by protecting from loss of nerves cells, ie a neuroprotective drug.
The purpose of this study is to assess the efficacy of amiloride as a neuroprotective drug in optic neuritis
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Double Blind Randomised Control Trial on Neuroprotection of Amiloride in Optic Neuritis|
- Scanning laser polarimetry determined retinal nerve fibre layer thickness [ Time Frame: Baseline, 6 and 12 months ] [ Designated as safety issue: No ]
The primary outcome will be difference in retinal nerve fibre thickness at 6 months between affected eye and non-affected fellow eye at baseline between the amiloride and placebo group.
An additional measure will be made at 12 months
- Optical coherence tomography determined difference in retinal nerve fibre layer thickness. [ Time Frame: Baseline, 6 and 12 months ] [ Designated as safety issue: No ]Difference in thickness at 6 months and 12 months between affected eye and non-affected fellow eye at baseline, between the amiloride and placebo group
- Differences between the amiloride and placebo groups in non-conventional MRI surrogate marker of white matter and grey matter injury and connectivity by 3T scanning. [ Time Frame: Baseline, 6 and 12 months ] [ Designated as safety issue: No ]
- Diffusion weighted imaging (DWI) - measures; 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 volume
- Magnetic resonance spectroscopy (MRS) measures of N-acetyl aspartate (NAA) in the visual cortex
- Resting state functional MRI (RS fMRI) patterns of activity
- Magnetisation transfer imaging (MTI) derived magnetisation transfer ratio (MTR) of the white and grey matter
- Visual Function [ Time Frame: Baseline, 6 and 12 months ] [ Designated as safety issue: No ]
- High and low contrast (2.5% and 1.25%) visual acuity.
- Farnsworth Munsell 100 Hue (FM100) colour vision test.
- Visual Electrophysiology [ Time Frame: 0 and 6 months ] [ Designated as safety issue: No ]Differences in visually evoked potential and pattern electro-retinogram between the amiloride and placebo groups as additional measures of visual function
- Quality of life questionnaires [ Time Frame: Baseline, 6 and 12 months ] [ Designated as safety issue: No ]
- 25 point national institutes for health visual function questionnaire
- 10 point neuro ophthalmic supplement.
|Study Start Date:||February 2013|
|Estimated Study Completion Date:||February 2015|
|Estimated Primary Completion Date:||September 2014 (Final data collection date for primary outcome measure)|
Active Comparator: Amiloride
Amiloride capsules 10mg once per day for 5 months
Other Name: Midamor
Placebo Comparator: Placebo
Placebo capsules one per day for 5 months
Placebo capsule identical in appearance to Amiloride 10mg capsule
Multiple sclerosis (MS), an inflammatory condition of the nervous system, is the most common cause of disability in people of working age in the western world. In addition to the inflammatory episodes in MS, axonal and neuronal damage occurs. It is this axonal loss which is thought to be the major pathological substrate for disability in MS.
Acute inflammatory demyelinating optic neuritis is a common event in multiple sclerosis. Following optic neuritis there is axonal loss in the optic nerve and retina, which if severe can result in a poor visual recovery. Uniquely amongst central nervous system (CNS) structures, the structural and functional changes in the eye during and following optic neuritis provide a sensitive way of observing neurodegeneration and testing the effectiveness of potential neuroprotective agents. In optic neuritis it has been shown that thinning of the retinal nerve fibre layer takes place, and by 6 months this thinning is established and has largely stabilised. This represents axonal loss in the anterior visual system. The degree of this thinning has been shown to correlate with the amount of vision recovered following optic neuritis, the more thinning that occurs, the poorer the outcome. The thickness of the retinal nerve fibre layer can be measured by the simple scanning techniques of scanning laser polarimetry (GDx) and optical coherence tomography (OCT).
Axonal loss in MS is likely to be multifactorial, but a key end point is the influx of sodium and calcium ions. Recent research suggests that in the inflammatory environment of optic neuritis, the acid sensing ion channel may have an important role in this influx of sodium and calcium, and therefore in axonal loss in MS. The drug amiloride, already in use as a diuretic, is a known blocker of this ion channel. The investigators have identified through laboratory and early clinical research in humans that by blockade of the acid sensing ion channel, amiloride may be neuroprotective in optic neuritis and MS.
The investigators primary objective is to assess the neuroprotective efficacy of amiloride in optic neuritis through the surrogate measure of retinal nerve fibre layer measurement. Secondary objectives are to assess markers of neurodegeneration in ON and the neuroprotective effect of amiloride through non-conventional MRI outcomes, to assess if amiloride improves functional and visual outcome following optic neuritis, and to confirm optic neuritis as a sensitive and efficient model for neuroprotection in a clinical trial framework.
46 Participants will be recruited to receive either amiloride, or an identical placebo capsule for 5 months. The primary outcome will be measured at 6 months, with a further measure at 12 months.
Should this trial show a significant benefit from amiloride in optic neuritis, it will be an important first step in developing neuroprotective therapies in optic neuritis and MS and potentially this could have a significant impact on people with MS and their carers.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01802489
|Contact: Justin McKee, MBChB||01865 firstname.lastname@example.org|
|John Radcliffe Hospital||Recruiting|
|Oxford, United Kingdom, OX3 9DU|
|Contact: Justin McKee, MBChB MRCP 01865231907 email@example.com|
|Principal Investigator: Matthew Craner, MBChB PhD|
|Principal Investigator:||Matthew Craner, MBChB PhD||University of Oxford|