Objective:

To develop a methodology to reduce the impact of pseudoexacerbations on annualized relapse rates in the ULTIMATE trials.

Background:

The primary endpoint in relapsing multiple sclerosis (MS) trials involves reducing annualized relapse rate (ARR), which may be prone to noise from pseudoexacerbations: symptom recrudescence events meeting relapse criteria without focal inflammation. This leads to a paradox in high efficacy therapy trials where relapses outnumber MRI lesions.

Design/Methods:

A higher stringency relapse definition was tested post-hoc in ULTIMATE: Criteria 1: increase of >0.5 points in EDSS score (unless EDSS=0, then increase of ≥1 point). [AND] Criteria 2: ≥2 points increase on one appropriate symptom-matched FS or 1 point on ≥2 appropriate FS. [AND] Criteria 3 & 4: EDSS or FSS change must be higher than prior scores. [AND] Criteria 5: confirmed relapse cannot have occurred within 2-months before/after any infection event. [AND] Criteria 6: relapse excluded if negative for Gd+ or n/e T2 lesions within 5 weeks of symptomatic event. Relapse counts were modeled using generalized estimating equations.

Results:

Re-baselining at week 24 decreased the proportion of ublituximab-treated participants with n/e T2 lesions by 93% (44.8% vs 3.1%), but only reduced the proportion of participants with relapse by traditional criteria by 16% (13.5% vs 11.4%), suggesting a contribution by pseudoexacerbations. Original ARR reduction in the ULTIMATE trials (ublituximab vs teriflunomide) was 54.2%. After applying the redefined relapse criteria, overall ARR reduction (0-96 weeks) increased to 60.1% (rate ratio [RR] 0.399[0.274, 0.580], p<0.0001; ARR: teriflunomide 0.138, and ublituximab 0.055), which further increased at 48-96 weeks to 66.4% (RR 0.336[0.204, 0.551], p<0.0001; ARR: teriflunomide 0.142, and ublituximab 0.048), aligning closer to MRI results.

Conclusions:

Increased stringency of MS relapse definition provides a truer assessment of clinical efficacy, and the improved signal to noise ratio of relapse outcomes has implications for relapsing MS trial design and power calculations.