Assessment of Clinically Meaningful Improvements in Self-Reported Walking Ability in Participants with Multiple Sclerosis: Results from the Randomized, Double-Blind, Phase III ENHANCE Trial of Prolonged-Release Fampridine.

Abstract

Background Walking impairment is a hallmark of multiple sclerosis (MS). It afects>90% of individuals over time, reducing independence and negatively impacting health-related quality of life, productivity, and daily activities. Walking impairment is consistently reported as one of the most distressing impairments by individuals with MS. Prolonged-release (PR)-fampridine previously has been shown to improve objectively measured walking speed in walking-impaired adults with MS. The impact of PR-fampridine from the perspective of the individual with MS warrants full and detailed examination. Objective The objective of this study was to evaluate whether PR-fampridine has a clinically meaningful efect on selfreported walking ability in walking-impaired participants with MS. Methods ENHANCE was a phase III, randomized, double-blind, placebo-controlled study of PR-fampridine 10 mg twice daily in walking-impaired individuals age 18–70 years with either relapsing or progressive forms of MS and an Expanded Disability Status Scale (EDSS) score of 4.0–7.0 at screening. Participants were stratifed by EDSS score (≤6.0 or 6.5–7.0) at randomization to ensure a balanced level of disability in the treatment groups. The primary endpoint was the proportion of participants with a mean improvement in the 12-item Multiple Sclerosis Walking Scale (MSWS-12) score exceeding the predefned threshold for clinically meaningful improvement (≥8 points) over 24 weeks. Secondary endpoints included the proportion with≥15% improvement in Timed Up and Go (TUG) speed, and mean changes in Multiple Sclerosis Impact Scale physical impact subscale (MSIS-29 PHYS), Berg Balance Scale (BBS), and ABILHAND scores over 24 weeks. Results In total, 636 participants with MS were randomized (PR-fampridine, n=317; placebo, n=319; modifed intention-totreat sample: PR-fampridine, n=315; placebo, n=318). At baseline in the PR-fampridine and placebo groups, 46% and 51% had a progressive form of MS, median [range] EDSS scores were 6.0 [4.0–7.0] and 5.5 [4.0–7.0], mean [range] MSWS-12 scores were 63.6 [0–100] and 65.4 [0–100], and mean [range] TUG speed was 0.38 [0.0–1.0] and 0.38 [0.0–1.2] feet/s, respectively. A signifcantly higher percentage of PR-fampridine-treated participants (136/315 [43.2%]) had clinically meaningful improvement in MSWS-12 score over 24 weeks versus placebo (107/318 [33.6%]; odds ratio 1.61 [95% confdence interval 1.15–2.26]; p=0.006). For PR-fampridine versus placebo, signifcantly more participants had a≥15% improvement in TUG speed, and there was signifcantly greater mean improvement in MSIS-29 PHYS score (p<0.05); numerical improvements that were not statistically signifcant were observed in BBS/ABILHAND. Adverse events that were more common in the PR-fampridine group than placebo group (diference≥3%) by Medical Dictionary for Regulatory Activities (MedDRA®) Preferred Term were urinary tract infection and insomnia. There were no seizures reported. Conclusions PR-fampridine treatment resulted in sustained, clinically meaningful improvements over 24 weeks in selfreported walking and functional ability in walking-disabled participants with MS. ClinicalTrials.gov Identifer NCT02219932.