title: Amiloride Clinical Trial In Optic Neuritis (ACTION) protocol: a randomised, double blind, placebo controlled trial.
abstract: BACKGROUND
  Neurodegeneration is a widely accepted contributor to the development of long-term disability in multiple sclerosis (MS). While current therapies in MS predominantly target inflammation and reduce relapse rate they have been less effective at preventing long-term disability. The identification and evaluation of effective neuroprotective therapies within a trial paradigm are key unmet needs. Emerging evidence supports amiloride, a licenced diuretic, as a neuroprotective agent in MS through acid sensing ion channel blockade. Optic neuritis (ON) is a common manifestation of MS with correlates of inflammation and neurodegeneration measurable within the visual pathways. Amiloride Clinical Trial In Optic Neuritis (ACTION) will utilise a multimodal approach to assess the neuroprotective efficacy of amiloride in acute ON.
  
  
  METHODS
  46 patients will be recruited within 28 days from onset of ON visual symptoms and randomised on a 1:1 basis to placebo or amiloride 10 mg daily. Double-blinded treatment groups will be balanced for age, sex and visual loss severity by a random-deterministic minimisation algorithm. The primary objective is to demonstrate that amiloride is neuroprotective in ON as assessed by scanning laser polarimetry of the peripapillary retinal nerve fibre layer (RNFL) thickness at 6 months in the affected eye compared to the unaffected eye at baseline. RNFL in combination with further retinal measures will also be assessed by optical coherence tomography. Secondary outcome measures on brain MRI will include cortical volume, diffusion-weighted imaging, resting state functional MRI, MR spectroscopy and magnetisation transfer ratio. In addition, high and low contrast visual acuity, visual fields, colour vision and electrophysiology will be assessed alongside quality of life measures.
  
  
  BACKGROUND
  Ethical approval was given by the south central Oxford B research ethics committee (REC reference: 13/SC/0022). The findings from ACTION will be disseminated through peer-reviewed publications and at scientific conferences.
  
  
  BACKGROUND
  EudraCT2012-004980-39, ClinicalTrials.gov Identifier: NCT01802489.
authors.affiliation: Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Justin B
authors.initials: JB
authors.lastname: McKee
authors.affiliation: Oxford Eye Hospital, John Radcliffe Hospital, Oxford, UK.
authors.forename: John
authors.initials: J
authors.lastname: Elston
authors.affiliation: Department of Clinical Neuroscience, University of Nottingham Medical School, Queens Medical Centre, Nottingham, UK.
authors.forename: Nikos
authors.initials: N
authors.lastname: Evangelou
authors.affiliation: Centre for Statistics in Medicine, University of Oxford, Oxford, UK.
authors.forename: Stephen
authors.initials: S
authors.lastname: Gerry
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Lars
authors.initials: L
authors.lastname: Fugger
authors.affiliation: Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kennard
authors.affiliation: Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK Nuffield Department of Clinical Neurosciences, Oxford Centre for Functional MRI of the Brain (FMRIB), University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Yazhuo
authors.initials: Y
authors.lastname: Kong
authors.affiliation: Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Palace
authors.affiliation: Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Craner
mesh_terms: D000293:Adolescent; D000328:Adult; D000584:Amiloride / Q000008:administration & dosage*; D004232:Diuretics / Q000008:administration & dosage; D004311:Double-Blind Method; D004739:England; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000150:complications*; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D009902:Optic Neuritis / Q000188:drug therapy*; D011788:Quality of Life; D012107:Research Design; D012160:Retina / Q000503:physiopathology*; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult
chemical_list: D004232:Diuretics; D018696:Neuroprotective Agents; D000584:Amiloride