No abstract

Background and Objectives:Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy, in PMS. In this post-hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype, and (3) associations between OCT and MRI measures of neurodegeneration.Methods:In the multi-center, double blinded SPRINT-MS trial, participants with SPMS or PPMS were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations.Results:134 PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07±0.23 µm/year) vs. placebo group (-0.32±0.20 µm/year, p=0.003). This effect predominated in the PPMS cohort (Ibudilast: -0.08±0.29 µm/year vs placebo: -0.60±0.29 µm/year, a decrease of 87%, p<0.001), and was not detected in the SPMS cohort (Ibudilast: -0.21±0.28 µm/year vs placebo: -0.14±0.27 µm/year, p=0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r=0.27, r=0.26, and r=0.20 respectively; p<0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%.Discussion:Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS.Classification of evidence:This study provides Class II evidence that ibudilast reduces composite ganglion cell and inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with progressive MS but not those with secondary progressive MS.