Patients With Multiple Sclerosis Show Willingness to Trade-Off Disease Progression for Improvements in Fatigue

Robert J. Fox, MD

Using data from a discrete choice experiment (DCE), post-hoc findings from the phase 3 OPTIMUM trial (NCT02425644) indicated that patients with relapsing multiple sclerosis (MS) would accept decreases in time to MS progression for a change in fatigue equal to the 3.57-point change observed in the original analysis. Above all, these observations highlighted the level of disruption caused by fatigue and the importance of fatigue treatment for this patient population.

In the trial, patients with MS were randomly assigned 1:1 to 20 mg of ponesimod (Ponvory; Janssen) or 14 mg of teriflunomide (Aubagio; Sanofi) once daily and the placebo for 108 weeks, with a 14-day gradual up-titration of ponesimod starting at 2 mg and were assessed at a follow-up period of 30 days. Originally reported in early 2021, the study’s main finding showed that ponesimod reduced annualized relapse rate (ARR) by 30.5% relative to teriflunomide. Secondary end points such as the Fatigue Symptom and Impact Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) was lower for fatigue symptoms in the ponesimod group than in the teriflunomide group at week 108, with least square means of 0.01 vs 3.56 (P = .002).

Led by Robert J. Fox, MD, neurologist, Mellen Center for Multiple Sclerosis, and Vice-Chair for Research, Neurological Institute, Cleveland Clinic, the web-based DCE estimated the maximum acceptable change in annual relapses and maximum acceptance change in time to MS progression that patients would accept for changes in cognitive and physical fatigue. The maximum acceptable increase in annual relapses was the change in ARR that patients with MS would regard as equally as important as a given change in cognitive or physical fatigue.

The DCE sample included 817 patients that had a mean age approximately 5 years higher, and included a higher proportion of females. DCE participants also reported a greater level of baseline fatigue, with a mean FSIQ-RMS-S score of 54.4 vs 31.9 for OPTIMUM patients treated with ponesimod and 32.8 for OPTIMUM patients treated with teriflunomide. Also, this cohort had more active disease than the original OPTIMUM sample (mean, 3.9 vs 1.7 relapses in the previous 2 years).

Using physical fatigue as the DCE analog for FSIQ-RMS-S, on average across the 3 physical fatigue levels, a 3.57-point change in score was equal in importance to an increase of 0.12 (95% CI, 0.10-0.13) relapses per year. For those with lower levels of physical fatigue, otherwise representative of patients in OPTIMUM at baseline, the corresponding increase was 0.06 (95% CI, 0.03-0.09) relapses per year. For higher levels of physical fatigue, the corresponding increase in relapse rate was 0.21 (95% CI, 0.18-0.25) relapses per year.

When cognitive fatigue was used as an analog, a 3.57-point change in FSIQ-RMS-S was equal in importance to an increase of 0.12 (95% CI, 0.10-0.13) relapses/year. For lower and moderate levels of cognitive fatigue, the corresponding increase was 0.09 (95% CI, 0.05-0.13) and 0.10 (95% CI, 0.07-0.13) relapses/year. For higher levels, the corresponding increase was higher, at 0.15 (95% CI, 0.12-0.18) relapses/year.

"The relapse values are similar to the treatment differences in ARR of 0.088 (confirmed relapses) and 0.099 (confirmed and unconfirmed relapses) in OPTIMUM, which suggests that patients would regard the improvement in ARR caused by ponesimod compared to teriflunomide as equal in importance to the difference in change in fatigue caused by ponesimod compared to teriflunomide," Fox et al wrote. "This consistency helps offset the absence of data regarding relapse severity in the DCE population. For a fatigue level of ‘quite a bit of difficulty,’ participants would be willing to accept larger increases in relapse rate and decreases in time to MS progression to reduce fatigue."

REFERENCES
1. Fox RJ, Tervonen T, Phillips-Beyer A, et al. The relevance of fatigue to relapse rate in multiple sclerosis: applying patient preference to the OPTIMUM trial. 2023;29(3). doi:10.1177/13524585221140270
2. Kappos L, Fox RJ, Burcklen M, et al. Ponesimod compared with teriflunomide in patients with relapsing multiple sclerosis in the active-comparator phase 3 OPTIMUM study. JAMA Neurol. published online March 29, 2021. doi: 10.1001/jamaneurol.2021.0405