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. CONCLUSION: 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.
RCT Entities:
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. CONCLUSION: 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: Amy T Waldman; Girish Hiremath; Robert A Avery; Amy Conger; Stacy L Pineles; Michael J Loguidice; Lauren S Talman; Kristin M Galetta; Michael J Shumski; James Wilson; E'tona Ford; Amy M Lavery; Darrel Conger; Benjamin M Greenberg; Jonas H Ellenberg; Elliot M Frohman; Laura J Balcer; Peter A Calabresi Journal: Mult Scler Relat Disord Date: 2013-05-01 Impact factor: 4.339
Authors: Kathryn C Fitzgerald; Kicheol Kim; Matthew D Smith; Sean A Aston; Nicholas Fioravante; Alissa M Rothman; Stephen Krieger; Stacey S Cofield; Dorlan J Kimbrough; Pavan Bhargava; Shiv Saidha; Katharine A Whartenby; Ari J Green; Ellen M Mowry; Gary R Cutter; Fred D Lublin; Sergio E Baranzini; Philip L De Jager; Peter A Calabresi Journal: Brain Date: 2019-09-01 Impact factor: 13.501
Authors: Reiko E Sakai; Daniel J Feller; Kristin M Galetta; Steven L Galetta; Laura J Balcer Journal: J Neuroophthalmol Date: 2011-12 Impact factor: 3.042
Authors: James Nguyen; Alissa Rothman; Kathryn Fitzgerald; Anna Whetstone; Stephanie Syc-Mazurek; Jannelle Aquino; Laura J Balcer; Elliot M Frohman; Teresa C Frohman; Ciprian Crainiceanu; Meghan Beier; Scott D Newsome; Peter A Calabresi; Shiv Saidha Journal: Curr Eye Res Date: 2018-05-01 Impact factor: 2.424