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 affects > 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 effect on self-reported 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 stratified 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 predefined 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; modified intention-to-treat 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 significantly 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% confidence interval 1.15-2.26]; p = 0.006). For PR-fampridine versus placebo, significantly more participants had a ≥ 15% improvement in TUG speed, and there was significantly greater mean improvement in MSIS-29 PHYS score (p < 0.05); numerical improvements that were not statistically significant were observed in BBS/ABILHAND. Adverse events that were more common in the PR-fampridine group than placebo group (difference ≥ 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 self-reported walking and functional ability in walking-disabled participants with MS. CLINICALTRIALS.

Gov identifier: NCT02219932.

Conflict of interest statement

Conflict of interest

Jeremy Hobart has received consulting/advisor fees, grants, honoraria, support for clinical service delivery, or research support from Acorda, Biogen, Brickell Biotech, GBT, Merck Serono, MS Society of Great Britain and Northern Ireland, Novartis, Roche, Tigercat, and Vantia; his hospital received a grant from Biogen to assist in the development of clinical service for people with MS and the university received a grant to conduct data analysis, and he received honoraria for attending PR-fampridine advisory boards and payment from Biogen for lectures on MS and PR-fampridine. Tjalf Ziemssen has received grants and personal fees from Bayer, Biogen, Genzyme, Novartis, and Teva; and personal fees from Almirall, GlaxoSmithKline, Merck, and Roche. Peter Feys has received advisory board fees from Biogen; speaker fees from Excemed and Paradigms; and fees for providing educational materials from Neurocompass. Michael Linnebank has received grants to fund a distinct study on PR-fampridine from Biogen, and support for travel and fees paid to his department for attendance at a PR-fampridine steering board. Andrew D. Goodman has received personal fees from AbbVie, Acorda, Adamas, Atara, Avanir, Bayer, Biogen, Celgene, EMD Serono, Novartis, Roche, Sanofi-Genzyme, Sun, and Teva. His institution (University of Rochester) has received research support for conducting clinical trials from Acorda, Biogen, EMD Serono, Novartis, Ono, Roche, Sanofi-Genzyme, and Teva. Rachel Farrell has received advisory fees from Biogen; consulting and principal investigator fees from Canbex; and speaker fees from Allergan PLC, GW Pharma, Merck, and Teva. Raymond Hupperts has received grants and honoraria for advisory boards from Biogen, Merck, and Sanofi-Genzyme. Andrew R. Blight was an employee of and holds stock/stock options in Acorda. Veronica Englishby, Manjit McNeill, Ih Chang, and Jacob Elkins are employees of and hold stock/stock options in Biogen. Gabriel Lima was an employee of Biogen at the time the study was conducted and the manuscript drafted; holds stock/stock options in Biogen; and is a current employee of Amgen.

Ethical approval

The study was conducted according to the US Code of Federal Regulations Parts 50, 54, 56, and 312 Subpart D; the International Conference on Harmonisation guideline on Good Clinical Practice (E6); the European Union Clinical Trial Directive 2001/20/EC; the principles of the Declaration of Helsinki; and, where applicable, the European Directives 2001/20 and 2005/28 in relation to conduct of clinical trials and investigational medicinal products. The trial was registered with ClinicalTrials.gov (NCT02219932).

Informed consent

Written informed consent was obtained from each individual before study participation.

Figures

Fig. 1

Participant disposition. AE adverse event, BID twice daily, PR prolonged-release. a1 patient randomized to PR-fampridine withdrew from the study before dosing (reason: consent withdrawn). bPatients who completed the 24-week double-blind treatment period and 2-week off-treatment follow-up visit calculated as follows: 317 − 51 = 266. A total of 271 participants completed the 24-week treatment period (Weeks 0–24). cPatients who completed the 24-week double-blind treatment period and 2-week off-treatment follow-up visit calculated as follows: 319 − 65 = 254. A total of 258 participants completed the 24-week treatment period (Weeks 0–24)

Fig. 2

Estimated proportion of study participants who met each threshold of mean MSWS-12 score change over 24 weeks in the modified intention-to-treat sample. The MSWS-12 was transformed to a 0–100 scale; higher score = greater walking limitation. Negative change indicates improvement. Estimated percentages were based on binomial proportions. Multiple imputation was used for missing post-baseline data. Nominal p-values for PR-fampridine vs. placebo are from a logistic regression model adjusted for covariates (see Sect. 2). MSWS-12 12-item Multiple Sclerosis Walking Scale, PR prolonged-release

Fig. 3

LSM changes in MSWS-12 score over 24 weeks in the modified intention-to-treat sample. Negative change indicates improvement. Multiple imputation was used for missing post-baseline data except for during follow-up where observed data were used. Error bars indicate SE. DB double-blind, LSM least squares mean, MSWS-12 12-item Multiple Sclerosis Walking Scale, PR prolonged-release, SE standard error

Fig. 4

LSM percentage change in TUG speed over 24 weeks in the modified intention-to-treat sample. TUG speed is given in feet/s. Positive change indicates improvement. Multiple imputation was used for missing post-baseline data except for during follow-up where observed data were used. Error bars indicate SE. DB double-blind, LSM least squares mean, PR prolonged-release, SE standard error, TUG Timed Up and Go