Natural course of clinically isolated optic neuritis: implications for trial design

Abstract

Aims/Purpose: To characterize disease‐induced changes in the first six months after acute optic neuritis and to aid the design of future neuroprotection trials.Methods: Treatment‐independent analysis of the TONE trial cohort (NCT01962571), including 103 patients with acute optic neuritis and baseline high contrast visual acuity <0.5 dec. We analysed study visits at baseline and weeks 1, 4, 16 and 26 with mixed effects linear piece‐wise models to describe the dynamics of low contrast letter acuity, contrast sensitivity, visual fields, visually evoked potentials and macular and peripapillary retinal layer thicknesses. Sample size estimates are based on a two‐sided t‐test with α=0.05, power 80%, and treatment effects equal to 50% of the mean diseased induced change.Results: After baseline visual loss, there was improvement of visual function with thinning of inner and swelling of outer retinal layers. Clinical trials could reduce their required size by more than half when using macular ganglion cell and inner plexiform layer thinning (33 patients/group) over peripapillary retinal nerve fibre layer thinning (79/group) as the primary outcome. Similarly, trials of functional neuroprotection could reduce their size by more than 40% when employing the inter‐eye delta of 2.5% low‐contrast letter acuity (109/group) over the affected eye's value alone (189/group) as their outcome. The respective associations to vision‐related quality of life (NEI‐VFQ overall score) were similar (Pearson's |r| = 0.08 vs. 0.15 and 0.38 vs. 0.39). Because inner retinal layer thicknesses remained stable after four months but functional improvements continued up to month six, trials should follow up accordingly.Conclusions: The negative results of the TONE trial make its participants one of the best‐characterized and largest cohorts of acute optic neuritis. Our data show that future trials may benefit from substantial efficiency gains.