Multiple sclerosis relapse redefined: Effect of an MRI-supported relapse criterion on ublituximab outcomes in the ULTIMATE I and II trials

BACKGROUND: In relapsing multiple sclerosis trials, reductions in annualized relapse rate and gadolinium-enhancing lesions often diverge, potentially due to misclassification of pseudoexacerbations as relapses. We evaluated whether incorporating magnetic resonance imaging evidence into relapse definitions improves specificity and apparent treatment effect. OBJECTIVES: We performed post hoc analyses of the ULTIMATE I and II phase 3 trials comparing ublituximab versus teriflunomide. Relapses were adjudicated per protocol (Expanded Disability Status Scale/Functional System Scales criteria). We applied increasingly stringent clinical criteria and a magnetic resonance imaging-supported relapse definition (new T2 lesion). Annualized relapse rate was modeled using a generalized estimating equation with exposure offset. Power/sample size implications were estimated. RESULTS: Protocol-defined annualized relapse rate reduction with ublituximab was 54.2% (annualized relapse rate: 0.084 vs 0.183). Stringent clinical criteria modestly increased reduction to 60.1%. Magnetic resonance imaging-supported relapses markedly amplified the effect to 87.5% (rate ratio: 0.125), with Year 2 reduction to 92.8%. Most ublituximab relapses (77.3%) lacked magnetic resonance imaging activity versus teriflunomide (17.8%). Power analyses indicated approximately a two-thirds sample size reduction using magnetic resonance imaging-supported relapses. CONCLUSION: Requiring magnetic resonance imaging evidence substantially increases specificity of relapse ascertainment, unmasks treatment effects of high-efficacy therapy, and improves trial efficiency. Prospective validation of magnetic resonance imaging-supported relapse definitions as complementary/alternative endpoints in relapsing multiple sclerosis trials is warranted, plus further corroboration with other biomarkers of disease activity toward a truly biologically verified relapse definition.