Effects of Ibudilast on MRI Measures in the Phase 2 SPRINT-MS Study

Abstract

Objective: To determine whether ibudilast has an effect on brain volume and new lesions in progressive forms of multiple sclerosis (MS).

Methods: A randomized, placebo-controlled, blinded study evaluated ibudilast at a dose of up to 100 mg over 96 weeks in primary and secondary progressive MS. In this secondary analysis of a previously reported trial, secondary and tertiary endpoints included gray matter atrophy, new or enlarging T2 lesions as measured every 24 weeks, and new T1 hypointensities at 96 weeks. Whole brain atrophy measured by structural image evaluation, using normalization, of atrophy (SIENA) was a sensitivity analysis.

Results: A total of 129 participants were assigned to ibudilast and 126 to placebo. New or enlarging T2 lesions were observed in 37.2% on ibudilast and 29.0% on placebo (p = 0.82). New T1 hypointense lesions at 96 weeks were observed in 33.3% on ibudilast and 23.5% on placebo (p = 0.11). Gray matter atrophy was reduced by 35% for those on ibudilast vs placebo (p = 0.038). Progression of whole brain atrophy by SIENA was slowed by 20% in the ibudilast group compared with placebo (p = 0.08).

Conclusion: Ibudilast treatment was associated with a reduction in gray matter atrophy. Ibudilast treatment was not associated with a reduction in new or enlarging T2 lesions or new T1 lesions. An effect on brain volume contributes to prior data that ibudilast appears to affect markers associated with neurodegenerative processes, but not inflammatory processes.

Classification of evidence: This study provides Class II evidence that for people with MS, ibudilast does not significantly reduce new or enlarging T2 lesions or new T1 lesions.

Figure 1. CONSORT (Consolidated Standards of Reporting Trials) Diagram

A schematic of patient disposition in NN102/SPRINT-MS (NeuroNEXT 102/Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis).

Figure 2. New or Enlarging T2 by Category [0, 1, 2, 3+] Over 96 Weeks and Means at 24, 48, 72, and 96 Weeks

(A) Most study participants had a median 0 new or enlarging T2 lesions over 96 weeks, with no observed difference between treatment assignments. (B) For mean new or enlarging lesions, no differences were observed for each 24-week interval and summed intervals over 96 weeks.

Figure 3. T1 Hypointense Lesion Counts and Volume Changes Over 96 Weeks

Ibudilast was not associated with (A) fewer T1 lesion counts or (B) an improvement in T1 lesion volume over the 96-week study.

Figure 4. Gray Matter Fraction (GMF) and Percent Brain Volume Change (PBVC) by Treatment at 24, 48, 72, and 96 Weeks

(A) GMF atrophy was reduced for the ibudilast-assigned group over the 96 weeks. (B) Brain atrophy by SIENA was lower with ibudilast (p = 0.08). Brain MRI was obtained at baseline and every 6 months through week 96. SIENA was determined from week 24 to baseline, week 48 to week 24, week 72 to week 48, and week 96 to week 72. Slope with 95% confidence intervals (CIs) was determined using linear mixed models with disease subtype and concurrent use of disease-modifying therapy. The SIENA model also adjusted for baseline BPF.

Figure 5. Participant Change in Percent Brain Volume Change (PBVC) by Treatment Arm