Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis

Abstract

Background: There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood-brain barrier, with potential salutary effects in progressive multiple sclerosis.

Methods: We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.

Results: Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was -0.0010 per year with ibudilast and -0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.

Conclusions: In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942 .).

Figure 1.. Change in Whole-Brain Atrophy.

Panel A shows the change in whole-brain atrophy in each trial group as derived from a linear mixed model. Change was measured according to the mean brain parenchymal fraction between baseline and week 96 with the use of all available data. The inset shows the same data on an enlarged y axis, with shaded areas indicating 95% confidence intervals of the estimated slope. Panel B shows box-and-whisker plots of change in whole-brain atrophy at each time point. The upper and lower edges of the boxes correspond to the 75th and 25th percentiles, respectively. Within the boxes, the circles (for placebo) and plus signs (for ibudilast) correspond to the mean and the horizontal lines correspond to the 50th percentile (median). The upper and lower ends of the whiskers correspond to the highest value within 1.5 times the interquartile range of the 75th percentile and the lowest value within 1.5 times the interquartile range of the 25th percentile, respectively. The circles and plus signs outside the whiskers indicate outliers. In both panels, the black dashed horizontal line represents a value of no change in the brain parenchymal fraction.

Figure 2.. Disability Progression That Was Sustained for at Least 20 Weeks.

In this analysis, progression of disability was measured according to the score on the Expanded Disability Status Scale (EDSS; range, 0 to 10 in 0.5-point increments, with higher scores indicating more disability) with the use of Cox proportional-hazards regression. Confirmed disability progression was defined as an increase in the EDSS score of at least 1.0 point from baseline (or an increase of ≥0.5 points for patients with a baseline EDSS score of >5.0) that was sustained for at least 20 weeks. Shaded areas indicate 95% confidence intervals. Tick marks indicate censored data. The estimated number of patients at risk for disability progression in each group at each time point is given below the graph.