1. Introduction
Walking impairment is a common disability among persons with multiple sclerosis (MS) and has a negative impact on quality of life [
1- Souza A.
- Kelleher A.
- Cooper R.
- Cooper R.A.
- Iezzoni L.I.
- Collins D.M.
Multiple sclerosis and mobility-related assistive technology: systematic review of literature.
,
2- Kohn C.G.
- Baker W.L.
- Sidovar M.F.
- Coleman C.I.
Walking speed and health-related quality of life in multiple sclerosis.
]. Walking disability can reduce independence, with lower limb function identified as the most important bodily function in a study of persons with MS [
[3]- Heesen C.
- Böhm J.
- Reich C.
- Kasper J.
- Goebel M.
- Gold S.M.
Patient perception of bodily functions in multiple sclerosis: gait and visual function are the most valuable.
]. Prolonged-release (PR) oral fampridine, also known as extended release (dal)fampridine in the US, is currently the only drug approved to improve walking in persons with MS [
,
]. In two pivotal phase 3 clinical studies, treatment with PR-fampridine resulted in consistent increases in walking speed versus placebo (25.2% versus 4.7%;
P < 0.001), for study subjects assessed as responders (consistently faster Timed 25-Foot Walk [T25FW] times on treatment versus off treatment) [
[6]- Goodman A.D.
- Brown T.R.
- Krupp L.B.
- Schapiro R.T.
- Schwid S.R.
- Cohen R.
- Marinucci L.N.
- Blight A.R.
Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.
]. Improvements in the self-assessed 12-item Multiple Sclerosis Walking Scale (MSWS-12) were also reported for responders, independent of treatment assignment (nominal
P < 0.001) [
[7]- Goodman A.D.
- Brown T.R.
- Edwards K.R.
- Krupp L.B.
- Schapiro R.T.
- Cohen R.
- Marinucci L.N.
- Blight A.R.
A phase 3 trial of extended release oral dalfampridine in multiple sclerosis.
]. Subsequent open-label extension studies in responder subjects from the two pivotal phase 3 studies showed that the efficacy and safety of PR-fampridine was maintained over a mean exposure of 39.0 and 26.3 months, with improved walking speed compared with non-responders [
[8]- Goodman A.D.
- Bethoux F.
- Brown T.R.
- Schapiro R.T.
- Cohen R.
- Marinucci L.N.
- Henney 3rd, H.R.
- Blight A.R.
Long-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: results of open-label extensions of two phase 3 clinical trials.
].
Recent studies have demonstrated that the benefits of PR-fampridine may extend beyond walking speed. Improvements in arm function, physical and cognitive fatigue, mood and quality of life were reported in PR-fampridine–treated subjects with MS, who showed improvements in walking ability through the T25FW, MSWS-12 or 2-Minute Walk Test [
9- Allart E.
- Benoit A.
- Blanchard-Dauphin A.
- Tiffreau V.
- Thevenon A.
- Zephir H.
- Outteryck O.
- Lacour A.
- Vermersch P.
Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.
,
10- Pavsic K.
- Pelicon K.
- Ledinek A.H.
- Sega S.
Short-term impact of fampridine on motor and cognitive functions, mood and quality of life among multiple sclerosis patients.
]. The psychological benefits of PR-fampridine were also reported in the ENABLE study, a 48-week, real-world, open-label study [
[11]- Macdonell R.
- Nagels G.
- Laplaud D.A.
- Pozzilli C.
- de Jong B.
- Martins da Silva A.
- Nicholas R.
- Lechner-Scott J.
- Gaebler J.A.
- Agarwal S.
- Wang P.
- Yeh M.
- Hovenden M.
- Soelberg Sorensen P.
Improved patient-reported health impact of multiple sclerosis: the ENABLE study of PR-fampridine.
]; however, there have been no data from blinded, placebo-controlled studies in a similar setting.
The phase 2, 24-week, double-blind, randomised MOBILE study expanded upon the ENABLE study and was the first placebo-controlled study to evaluate the impact of PR-fampridine treatment on mobility, balance and the subject-perceived health impact of MS, using several self-assessed measures [
[12]- Hupperts R.
- Lycke J.
- Short C.
- Gasperini C.
- McNeill M.
- Medori R.
- Tofil-Kaluza A.
- Hovenden M.
- Mehta L.R.
- Elkins J.
Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial.
]. Results from the MOBILE study included greater median improvements from baseline in the 29-item Multiple Sclerosis Impact Scale (MSIS-29) physical subscale (PHYS) versus placebo. Additionally, a higher proportion of subjects treated with PR-fampridine achieved improvements in the clinically significant MSWS-12 ≥ 8-point reduction threshold [
[13]- Mehta L.
- McNeill M.
- Hobart J.
- Wyrwich K.W.
- Poon J.-L.
- Auguste P.
- Zhong J.
- Elkins J.
Identifying an important change estimate for the Multiple Sclerosis Walking Scale-12 (MSWS-12v1) for interpreting clinical trial results.
] versus placebo (
P = 0.0153) [
[12]- Hupperts R.
- Lycke J.
- Short C.
- Gasperini C.
- McNeill M.
- Medori R.
- Tofil-Kaluza A.
- Hovenden M.
- Mehta L.R.
- Elkins J.
Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial.
]. Adverse events were consistent with the established safety profile of PR-fampridine [
[12]- Hupperts R.
- Lycke J.
- Short C.
- Gasperini C.
- McNeill M.
- Medori R.
- Tofil-Kaluza A.
- Hovenden M.
- Mehta L.R.
- Elkins J.
Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial.
].
This analysis of the MOBILE study evaluated the effect of PR-fampridine versus placebo on the subject-perceived physical and psychological health impact of MS based on the 29 individual items of the MSIS-29. The self-administered MSIS-29 questionnaire contains a 20-item PHYS and a nine-item psychological impact subscale (PSYCH) and shows good variability, high internal consistency, high test-retest reliability and good responsiveness to interventions [
14- Hobart J.
- Lamping D.
- Fitzpatrick R.
- Riazi A.
- Thompson A.
The Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure.
,
15- Hobart J.
- Riazi A.
- Lamping D.
- Fitzpatrick R.
- Thompson A.
How responsive is the Multiple Sclerosis Impact Scale (MSIS-29)? A comparison with some other self report scales.
]. A post hoc analysis also evaluated MSWS-12 improvers – subjects who were treated with PR-fampridine and achieved the clinically significant ≥
8-point reduction threshold in MSWS-12 score.
4. Discussion
MS is a debilitating disease that can result in walking impairment [
1- Souza A.
- Kelleher A.
- Cooper R.
- Cooper R.A.
- Iezzoni L.I.
- Collins D.M.
Multiple sclerosis and mobility-related assistive technology: systematic review of literature.
,
19Impact of mobility impairment in multiple sclerosis 2 - patients' perspectives.
]. Previous studies have demonstrated an association between walking speed and quality of life, suggesting that greater walking disability leads to reduced quality of life [
[2]- Kohn C.G.
- Baker W.L.
- Sidovar M.F.
- Coleman C.I.
Walking speed and health-related quality of life in multiple sclerosis.
]. In the pivotal phase 3 clinical studies, PR-fampridine was shown to improve walking ability [
6- Goodman A.D.
- Brown T.R.
- Krupp L.B.
- Schapiro R.T.
- Schwid S.R.
- Cohen R.
- Marinucci L.N.
- Blight A.R.
Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial.
,
7- Goodman A.D.
- Brown T.R.
- Edwards K.R.
- Krupp L.B.
- Schapiro R.T.
- Cohen R.
- Marinucci L.N.
- Blight A.R.
A phase 3 trial of extended release oral dalfampridine in multiple sclerosis.
], while post-marketing and placebo-controlled studies also demonstrated improvements in dynamic and static balance [
12- Hupperts R.
- Lycke J.
- Short C.
- Gasperini C.
- McNeill M.
- Medori R.
- Tofil-Kaluza A.
- Hovenden M.
- Mehta L.R.
- Elkins J.
Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial.
,
20- Prosperini L.
- Gianni C.
- Fortuna D.
- Marchetti M.R.
- Pozzilli C.
Oral dalfampridine improves standing balance detected at static posturography in multiple sclerosis.
].
In MOBILE, PR-fampridine showed benefits in subjects with MS on subject-assessed walking ability assessed using the MSWS-12, including numerically larger median improvements compared with placebo [
[12]- Hupperts R.
- Lycke J.
- Short C.
- Gasperini C.
- McNeill M.
- Medori R.
- Tofil-Kaluza A.
- Hovenden M.
- Mehta L.R.
- Elkins J.
Prolonged-release fampridine and walking and balance in MS: randomised controlled MOBILE trial.
]. In addition to these benefits, results from the current analyses of the MOBILE study indicate that PR-fampridine treatment improved the self-assessed physical and psychological health impact of MS. PR-fampridine treatment resulted in mean reductions in the MSIS-29 PHYS and PSYCH subscale scores, with a higher percentage of study subjects showing improvements across the majority of the PHYS and PSYCH items versus placebo. Evaluation of the MSWS-12 improvers demonstrated that the physical and psychological benefits of PR-fampridine were improved to a greater extent in those who showed a clinically meaningful increase in walking speed.
Thresholds for clinically meaningful worsening in the MSIS-29 PHYS subscale score have been established in both the clinical trial and the community setting [
17- Phillips G.A.
- Wyrwich K.W.
- Guo S.
- Medori R.
- Altincatal A.
- Wagner L.
- Elkins J.
Responder definition of the Multiple Sclerosis Impact Scale physical impact subscale for patients with physical worsening.
,
18- Costelloe L.
- O'Rourke K.
- Kearney H.
- McGuigan C.
- Gribbin L.
- Duggan M.
- Daly L.
- Tubridy N.
- Hutchinson M.
The patient knows best: significant change in the physical component of the Multiple Sclerosis Impact Scale (MSIS-29 physical).
]. Clinically meaningful worsening in the MSIS-29 PHYS subscale score was reported as ≥
7.5 points in a clinical trial population [
[17]- Phillips G.A.
- Wyrwich K.W.
- Guo S.
- Medori R.
- Altincatal A.
- Wagner L.
- Elkins J.
Responder definition of the Multiple Sclerosis Impact Scale physical impact subscale for patients with physical worsening.
] and ≥
7.0 points in a community setting [
[18]- Costelloe L.
- O'Rourke K.
- Kearney H.
- McGuigan C.
- Gribbin L.
- Duggan M.
- Daly L.
- Tubridy N.
- Hutchinson M.
The patient knows best: significant change in the physical component of the Multiple Sclerosis Impact Scale (MSIS-29 physical).
], for subjects with MS and an EDSS score of 0 to 5 [
[17]- Phillips G.A.
- Wyrwich K.W.
- Guo S.
- Medori R.
- Altincatal A.
- Wagner L.
- Elkins J.
Responder definition of the Multiple Sclerosis Impact Scale physical impact subscale for patients with physical worsening.
]. For subjects based in a community setting with an EDSS score of 5.5 to 8, the clinically meaningful threshold for MSIS-29 PHYS subscale worsening was reported as ≥
8 points [
[18]- Costelloe L.
- O'Rourke K.
- Kearney H.
- McGuigan C.
- Gribbin L.
- Duggan M.
- Daly L.
- Tubridy N.
- Hutchinson M.
The patient knows best: significant change in the physical component of the Multiple Sclerosis Impact Scale (MSIS-29 physical).
]. A threshold for
improvement in the MSIS-29 PHYS subscale score has yet to be established, to the authors' knowledge. However, a ≥
7-point change in MSIS-29 PHYS subscale score provides a good estimate of subjects who may be experiencing clinically meaningful improvements in the MSIS-29 PHYS subscale. The current analysis showed that the majority of the PR-fampridine–treated MSWS-12 improver subjects (82%) also showed ≥
7-point mean improvement in the MSIS-29 PHYS subscale score over weeks 2 to 24 of treatment. Few subjects (11%,
n = 4) in the PR-fampridine MSWS-12 non-improver group met this threshold for improvement in the MSIS-29 PHYS subscale score. These post hoc results provide additional support that improvements in walking ability are consistent with better subject-reported physical functioning.
Progression of the MSIS-29 PHYS and PSYCH subscale scores for the PR-fampridine population were similar throughout the study, consistent with findings from the open-label, 48-week ENABLE study [
[11]- Macdonell R.
- Nagels G.
- Laplaud D.A.
- Pozzilli C.
- de Jong B.
- Martins da Silva A.
- Nicholas R.
- Lechner-Scott J.
- Gaebler J.A.
- Agarwal S.
- Wang P.
- Yeh M.
- Hovenden M.
- Soelberg Sorensen P.
Improved patient-reported health impact of multiple sclerosis: the ENABLE study of PR-fampridine.
]. Improvements observed across both the MSIS-29 PHYS and PSYCH subscale scores for PR-fampridine–treated subjects in this analysis are consistent with those reported by Hoogervorst et al., who described good correlation between PHYS and PSYCH subscale scores (
r = 0.62) in a large, independent population of persons with MS [
[21]- Hoogervorst E.L.
- Zwemmer J.N.
- Jelles B.
- Polman C.H.
- Uitdehaag B.M.
Multiple Sclerosis Impact Scale (MSIS-29): relation to established measures of impairment and disability.
]. A Swedish registry study of natalizumab also showed improvements across both the PHYS and PSYCH subscale scores after 24 months, indicating that physical health improvements are linked to definable psychological benefits in persons with MS [
[22]- Holmén C.
- Piehl F.
- Hillert J.
- Fogdell-Hahn A.
- Lundkvist M.
- Karlberg E.
- Nilsson P.
- Dahle C.
- Feltelius N.
- Svenningsson A.
- Lycke J.
- Olsson T.
A Swedish national post-marketing surveillance study of natalizumab treatment in multiple sclerosis.
]. It should be noted that the results assessing psychological impact in this analysis showed greater variability compared with the physical impact.
Results show that treatment with PR-fampridine improved the subject-perceived physical health impact of MS, extending findings from the open-label ENABLE study, which demonstrated significant improvements in the mean MSIS-29 PHYS subscale change from baseline versus placebo at weeks 12 and 24. Significant improvements in MSIS-29 PHYS subscale score were subsequently maintained throughout the 48 weeks of the ENABLE study [
[11]- Macdonell R.
- Nagels G.
- Laplaud D.A.
- Pozzilli C.
- de Jong B.
- Martins da Silva A.
- Nicholas R.
- Lechner-Scott J.
- Gaebler J.A.
- Agarwal S.
- Wang P.
- Yeh M.
- Hovenden M.
- Soelberg Sorensen P.
Improved patient-reported health impact of multiple sclerosis: the ENABLE study of PR-fampridine.
].
Consistent with the improvement in overall MSIS-29 PHYS subscale score, higher percentages of PR-fampridine–treated subjects demonstrated reductions in scores across 16 of the 20 individual MSIS-29 PHYS items versus placebo over 24 weeks, with differences being statistically significant for four items. When study subjects were analysed according to whether they achieved a clinically significant improvement on the MSWS-12 (≥8-point mean reduction), greater percentages of MSWS-12 improvers reported reductions across all of the 20 MSIS-29 PHYS items versus both the placebo and MSWS-12 non-improver populations over weeks 2 to 24. As a higher percentage of the MSWS-12 improver group reported improvements across items such as having to depend on others to do things, taking longer to do things and having to cut time on work/other activities, the greater independence gained through improved walking ability in these subjects may lead to a more active life and improved overall physical outcomes. The results of the MSIS-29 PHYS item-level analysis of the PR-fampridine–treated MSWS-12 improver subjects provide further insight into the impact of improved walking ability on the health-related quality of life of persons with MS.
The psychological benefits of PR-fampridine treatment reported here are also consistent with previous reports, with the ENABLE study demonstrating significant improvements (
P < 0.001) in the MSIS-29 PSYCH and 36-Item Short Form Health Survey mental component summary scores at weeks 12 and 24 versus subjects who did not receive treatment [
[11]- Macdonell R.
- Nagels G.
- Laplaud D.A.
- Pozzilli C.
- de Jong B.
- Martins da Silva A.
- Nicholas R.
- Lechner-Scott J.
- Gaebler J.A.
- Agarwal S.
- Wang P.
- Yeh M.
- Hovenden M.
- Soelberg Sorensen P.
Improved patient-reported health impact of multiple sclerosis: the ENABLE study of PR-fampridine.
]. As reported in previous studies, improvements in walking ability, arm function, fatigue, mood and quality of life following PR-fampridine treatment may contribute to the psychological benefits observed here [
9- Allart E.
- Benoit A.
- Blanchard-Dauphin A.
- Tiffreau V.
- Thevenon A.
- Zephir H.
- Outteryck O.
- Lacour A.
- Vermersch P.
Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.
,
10- Pavsic K.
- Pelicon K.
- Ledinek A.H.
- Sega S.
Short-term impact of fampridine on motor and cognitive functions, mood and quality of life among multiple sclerosis patients.
]. Further evaluation of the benefits observed with PR-fampridine in the MSIS-29 PSYCH item-level analysis demonstrated improvements across six of the nine PSYCH items compared with placebo over 24 weeks. It is worth noting that a higher percentage of PR-fampridine–treated and MSWS-12 improver subjects reported mean improvements for the MSIS-29 PSYCH item
feeling mentally fatigued versus placebo, consistent with findings from Allart et al., who reported significant and prolonged improvements in fatigue after 3 months of treatment with PR-fampridine [
[9]- Allart E.
- Benoit A.
- Blanchard-Dauphin A.
- Tiffreau V.
- Thevenon A.
- Zephir H.
- Outteryck O.
- Lacour A.
- Vermersch P.
Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life.
]. Interestingly, both MSWS-12 improver and non-improver study subjects reported greater mean improvements in
worries related to your MS compared with placebo.
The MOBILE study showed that PR-fampridine treatment was associated with consistent subject-reported improvements in the physical and psychological measures of MS versus placebo. Analysis of the MSWS-12 improver population indicated that subjects who experience clinically meaningful improvements in walking ability show greater physical and psychological quality of life benefits.
Limitations of this study include a small sample size, the exploratory nature of the study and that some of the analyses were performed post hoc. Evaluation of the study subjects following completion of the wash-out period could have further clarified whether the physical and psychological benefits versus placebo were attributable to PR-fampridine. The findings from this study need to be confirmed in a larger placebo-controlled study, which is currently underway.
Article info
Publication history
Published online: August 25, 2016
Accepted:
August 24,
2016
Received in revised form:
August 19,
2016
Received:
March 9,
2016
Copyright
© 2016 The Authors. Published by Elsevier B.V.