title: Inclusion of brain volume loss in a revised measure of 'no evidence of disease activity' (NEDA-4) in relapsing-remitting multiple sclerosis.
abstract: 'No evidence of disease activity' (NEDA), defined as absence of magnetic resonance imaging activity (T2 and/or gadolinium-enhanced T1 lesions), relapses and disability progression ('NEDA-3'), is used as a comprehensive measure of treatment response in relapsing multiple sclerosis (RMS), but is weighted towards inflammatory activity. Accelerated brain volume loss (BVL) occurs in RMS and is an objective measure of disease worsening and progression.
  
  
  
  To assess the contribution of individual components of NEDA-3 and the impact of adding BVL to NEDA-3 ('NEDA-4') METHODS: We analysed data pooled from two placebo-controlled phase 3 fingolimod trials in RMS and assessed NEDA-4 using different annual BVL mean rate thresholds (0.2%-1.2%).
  
  
  
  At 2 years, 31.0% (217/700) of patients receiving fingolimod 0.5 mg achieved NEDA-3 versus 9.9% (71/715) on placebo (odds ratio (OR) 4.07; p < 0.0001). Adding BVL (threshold of 0.4%), the respective proportions of patients achieving NEDA-4 were 19.7% (139/706) and 5.3% (38/721; OR 4.41; p < 0.0001). NEDA-4 status favoured fingolimod across all BVL thresholds tested (OR 4.01-4.41; p < 0.0001).
  
  
  
  NEDA-4 has the potential to capture the impact of therapies on both inflammation and neurodegeneration, and deserves further evaluation across different compounds and in long-term studies.
authors.affiliation: Neurology, Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital Basel, Basel, Switzerland ludwig.kappos@usb.ch.
authors.forename: Ludwig
authors.initials: L
authors.lastname: Kappos
authors.affiliation: Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: De Stefano
authors.affiliation: University of Ottawa and Ottawa Hospital Research Institute, Ottawa, ON, Canada.
authors.forename: Mark S
authors.initials: MS
authors.lastname: Freedman
authors.affiliation: Multiple Sclerosis Center, University of California, San Francisco, CA, USA.
authors.forename: Bruce Ac
authors.initials: BA
authors.lastname: Cree
authors.affiliation: Medical Image Analysis Centre, University of Basel, University Hospital Basel, Basel, Switzerland.
authors.forename: Ernst-Wilhelm
authors.initials: EW
authors.lastname: Radue
authors.affiliation: Medical Image Analysis Centre, University of Basel, University Hospital Basel, Basel, Switzerland; Department of Neurology, DKD Helios Klinik Wiesbaden, Wiesbaden, Germany.
authors.forename: Till
authors.initials: T
authors.lastname: Sprenger
authors.affiliation: Biostatistics Unit, Department of Health Sciences, University of Genoa, Genoa, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Sormani
authors.affiliation: Oxford PharmaGenesis, Oxford, UK.
authors.forename: Terence
authors.initials: T
authors.lastname: Smith
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Dieter A
authors.initials: DA
authors.lastname: Häring
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Daniela
authors.initials: D
authors.lastname: Piani Meier
authors.affiliation: Novartis Pharma AG, Basel, Switzerland.
authors.forename: Davorka
authors.initials: D
authors.lastname: Tomic
mesh_terms: D000293:Adolescent; D000328:Adult; D001284:Atrophy; D001921:Brain / Q000000981:diagnostic imaging* / Q000473:pathology; D017326:Clinical Trials, Phase III as Topic; D005260:Female; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000000981:diagnostic imaging* / Q000188:drug therapy; D009929:Organ Size; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride
keywords: Atrophy; NEDA; brain; fingolimod; multiple sclerosis