title: Low-contrast acuity measures visual improvement in phase 3 trial of natalizumab in relapsing MS.
abstract: OBJECTIVE
  Low-contrast letter acuity has demonstrated treatment effects for sustained visual loss in trials of natalizumab for relapsing multiple sclerosis (MS). To test new therapies that may involve neuroprotection and repair, it will be essential for outcome measures to detect improvement as well as loss of visual function. We determined the effects of natalizumab on the frequency and cumulative probability of visual improvement using low-contrast letter acuity a prespecified tertiary outcome measure in AFFIRM.
  
  
  METHODS
  AFFIRM was a randomized, double-blind, placebo-controlled, phase 3 trial that evaluated efficacy and safety of natalizumab (n=627) vs. placebo (n=315) in relapsing-remitting MS. Binocular acuities were measured at low-contrast (1.25%, 2.5%) and high-contrast visual acuity (VA). Improvement was defined as 12-week sustained increases from baseline. Clinically meaningful change for primary analyses was pre-defined as 7-letter improvement for low-contrast acuity and 5-letter improvement for VA based upon previous studies.
  
  
  RESULTS
  Compared to placebo, cumulative probabilities of sustained visual improvement were greater in the natalizumab group by 57% for 2.5% contrast (21.7% vs. 14.0%; HR=1.57; 95% CI: 1.11-2.22; P=0.012) and 39% for 1.25% contrast (32.5% vs. 25.0%; HR=1.39; 95% CI: 1.07-1.82; P=0.014). The 5- and 10-letter low-contrast assessments did not show treatment differences. High-contrast VA was insensitive to changes over time and treatment effects.
  
  
  CONCLUSIONS
  Low-contrast letter acuity detected treatment effects on sustained visual improvement in patients with relapsing MS. The ability to detect visual improvement and loss makes low-contrast acuity an important measure for future trials assessing the impact of therapy on this outcome and the potential of a therapy for neuroprotection and repair.
authors.affiliation: Department of Neurology, University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA 19104, USA. lbalcer@mail.med.upenn.edu
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Balcer
authors.forename: Steven L
authors.initials: SL
authors.lastname: Galetta
authors.forename: Chris H
authors.initials: CH
authors.lastname: Polman
authors.forename: Eric
authors.initials: E
authors.lastname: Eggenberger
authors.forename: Peter A
authors.initials: PA
authors.lastname: Calabresi
authors.forename: Annie
authors.initials: A
authors.lastname: Zhang
authors.forename: James V
authors.initials: JV
authors.lastname: Scanlon
authors.forename: Robert
authors.initials: R
authors.lastname: Hyde
mesh_terms: D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D004311:Double-Blind Method; D016903:Drug Monitoring / Q000379:methods*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000150:complications / Q000188:drug therapy*; D000069442:Natalizumab; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D016896:Treatment Outcome; D014786:Vision Disorders / Q000175:diagnosis / Q000188:drug therapy* / Q000209:etiology; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000069442:Natalizumab