Effects of Ibudilast on Retinal Atrophy in Progressive Multiple Sclerosis Subtypes: Post Hoc Analyses of the SPRINT-MS Trial

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 multicenter, double-blind SPRINT-MS trial, participants with secondary progressive MS (SPMS) or primary progressive MS (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: One hundred thirty-four PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07 ± 0.23 µm/y) vs placebo group (-0.32 ± 0.20 µm/y, p = 0.003). This effect predominated in the PPMS cohort (ibudilast: -0.08 ± 0.29 µm/y vs placebo: -0.60 ± 0.29 µm/y, a decrease of 87%, p < 0.001) and was not detected in the SPMS cohort (ibudilast: -0.21 ± 0.28 µm/y vs placebo: -0.14 ± 0.27 µm/y, 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 + inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with primary progressive MS but not those with secondary progressive MS.

Figure 1. Change in GCIPL Thickness Over Time, by Treatment Group and PMS Subgroup, in the SPRINT-MS Clinical Trial

Lines represent estimated annual rates of ganglion cell + inner plexiform layer (GCIPL) change for the entire population (A), as well as the primary progressive multiple sclerosis (PPMS, B) and secondary progressive multiple sclerosis (SPMS, C) subgroups (placebo [green] and ibudilast [red] lines). Shaded areas represent the 95% confidence intervals (light gray or dark gray for overlapping confidence intervals). Rates were estimated using mixed-effects models with random intercepts and adjusted for age, sex, subtype, and disease duration. The lines are shown originating at 0 μm to show annual change from baseline. The x axis ranges from 0 to 1 to represent the estimated change over the course of 1 year.

Figure 2. Sample Size Graphs for Power vs Effect Size in a Combined Cohort and Subtypes

Models for sample size of future studies show the relationship between effect size and theoretical power in a combined cohort composed of participants with any form of progressive multiple sclerosis (MS) with a similar composition of the SPRINT-MS trial, of a cohort composed of participants with primary progressive multiple sclerosis (PPMS), and a cohort composed of participants with secondary progressive multiple sclerosis (SPMS).